Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by vla-4

ABSTRACT

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer&#39;s disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Ser. No. 60/116,923, filedJan. 22, 1999, and U.S. Ser. No. 60/160,999, filed Oct. 21, 1999; thedisclosures of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds which inhibit leukocyte adhesionand, in particular, leukocyte adhesion mediated by VLA-4.

REFERENCES

The following publications, patents and patent applications are cited inthis application as superscript numbers:

-   ¹ Hemler and Takada, European Patent Application Publication No.    330,506, published Aug. 30, 1989-   ² Elices, et al., Cell, 60:577-584 (1990)-   ³ Springer, Nature, 346:425-434 (1990)-   ⁴ Osborn, Cell, 62:3-6 (1990)-   ⁵ Vedder, et al., Surgery, 106:509 (1989)-   ⁶ Pretolani, et al., J. Exp. Med., 180:795 (1994)-   ⁷ Abraham, et al., J. Clin. Invest., 93:776 (1994)-   ⁸ Mulligan, et al., J. Immunology, 150:2407 (1993)-   ⁹ Cybulsky, et al., Science, 251:788 (1991)-   ¹⁰ Li, et al., Arterioscler. Thromb., 13:197 (1993)-   ¹¹ Sasseville, et al., Am. J. Path., 144:27 (1994)-   ¹² Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494 (1993)-   ¹³ Buddy, et al., Diabetes, 43:529 (1994)-   ¹⁴ Baron, et al, J. Clin. Invest., 93:1700 (1994)-   ¹⁵ Hamann, et al., J. Immunology, 152:3238 (1994)-   ¹⁶ Yednock, et al., Nature, 356:63 (1992)-   ¹⁷ Baron, et al., J. Exp. Med., 177:57 (1993)-   ¹⁸ van Dinther-Janssen, et al., J. Immunology, 147:4207 (1991)-   ¹⁹ van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52:672    (1993)-   ²⁰ Elices, et al., J. Clin. Invest., 93:405 (1994)-   ²¹ Postigo, et al., J. Clin. Invest., 89:1445 (1991)-   ²² Paul, et al., Transpl. Proceed., 25:813 (1993)-   ²³ Okarhara, et al., Can. Res., 54:3233 (1994)-   ²⁴ Paavonen, et al., Int. J. Can., 58:298 (1994) 25′-   ²⁵ Schadendorf, et al., J. Path., 170:429 (1993)-   ²⁶ Bao, et al., Diff., 52:239 (1993)-   ²⁷ Lauri, et al., British J. Cancer, 68:862 (1993)-   28 Kawaguchi, et al., Japanese J. Cancer Res., 83:1304 (1992)-   ²⁹ Kogan, et al., U.S. Pat. No. 5,510,332, issued Apr. 23, 1996-   ³⁰ International Patent Appl. Publication No. WO 96/01644

All of the above publications, patents and patent applications areherein incorporated by reference in their entirety to the same extent asif each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety.

2. State of the Art

VLA-4 (also referred to as α₄β₁ integrin and CD49d/CD29), firstidentified by Hemler and Takada¹ is a member of the β1 integrin familyof cell surface receptors, each of which comprises two subunits, an αchain and a β chain. VLA-4 contains an α4 chain and a β1 chain. Thereare at least nine β1 integrins, all sharing the same β1 chain and eachhaving a distinct a chain. These nine receptors all bind a differentcomplement of the various cell matrix molecules, such as fibronectin,laminin, and collagen. VLA-4, for example, binds to fibronectin. VLA-4also binds non-matrix molecules that are expressed by endothelial andother cells. These non-matrix molecules include VCAM-1, which isexpressed on cytokine-activated human umbilical vein endothelial cellsin culture. Distinct epitopes of VLA-4 are responsible for thefibronectin and VCAM-1 binding activities and each activity has beenshown to be inhibited independently.²

Intercellular adhesion mediated by VLA-4 and other cell surfacereceptors is associated with a number of inflammatory responses. At thesite of an injury or other inflammatory stimulus, activated vascularendothelial cells express molecules that are adhesive for leukocytes.The mechanics of leukocyte adhesion to endothelial cells involves, inpart, the recognition and binding of cell surface receptors onleukocytes to the corresponding cell surface molecules on endothelialcells. Once bound, the leukocytes migrate across the blood vessel wallto enter the injured site and release chemical mediators to combatinfection. For reviews of adhesion receptors of the immune system, see,for example, Springer³ and Osborn⁴.

Inflammatory brain disorders, such as experimental autoimmuneencephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, areexamples of central nervous system disorders in which theendothelium/leukocyte adhesion mechanism results in destruction tootherwise healthy brain tissue. Large numbers of leukocytes migrateacross the blood brain barrier (BBB) in subjects with these inflammatorydiseases. The leukocytes release toxic mediators that cause extensivetissue damage resulting in impaired nerve conduction and paralysis.

In other organ systems, tissue damage also occurs via an adhesionmechanism resulting in migration or activation of leukocytes. Forexample, it has been shown that the initial insult following myocardialischemia to heart tissue can be further complicated by leukocyte entryto the injured tissue causing still further insult (Vedder et al.⁵).Other inflammatory or medical conditions mediated by an adhesionmechanism include, by way of example, asthmas⁶⁻⁸, Alzheimer's disease,atherosclerosis⁹⁻¹⁰, AIDS dementia¹¹, diabetes¹²⁻¹⁴ (including acutejuvenile onset diabetes), inflammatory bowel disease¹⁵ (includingulcerative colitis and Crohn's disease), multiple sclerosis¹⁶⁻¹⁷,rheumatoid arthritis¹⁸⁻²¹, tissue transplantation²², tumormetastasis²³⁻²⁸, meningitis, encephalitis, stroke, and other cerebraltraumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardialischemia and acute leukocyte-mediated lung injury such as that whichoccurs in adult respiratory distress syndrome.

In view of the above, assays for determining the VLA-4 level in abiological sample containing VLA-4 would be useful, for example, todiagnosis VLA-4 mediated conditions. Additionally, despite theseadvances in the understanding of leukocyte adhesion, the art has onlyrecently addressed the use of inhibitors of adhesion in the treatment ofinflammatory brain diseases and other inflammatory conditions^(29,30).The present invention addresses these and other needs.

SUMMARY OF THE INVENTION

This invention provides compounds which bind to VLA-4. Such compoundscan be used, for example, to assay for the presence of VLA-4 in a sampleand in pharmaceutical compositions to inhibit cellular adhesion mediatedby VLA-4, for example, binding of VCAM-1 to VLA-4. The compounds of thisinvention have a binding affinity to VLA-4 as expressed by an IC₅₀ ofabout 1.5 μM or less (as measured using the procedures described inExample A below).

Accordingly, in one of its method aspects, this invention is directed toa method for treating a disease mediated by VLA-4 in a patient, whichmethod comprises administering a pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of formula Ia and/or Ib:

wherein, in formula Ia, R¹ and R², together with the carbon atom and Wto which they are bound respectively, are joined to form an aryl,cycloalkenyl, heteroaryl or heterocyclic group having at least fiveatoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group andoptionally containing or additionally containing in the case ofheteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur, and wherein theheteroaryl or heterocyclic group is mono-cyclic;

in formula Ib, R¹ and R², together with the carbon atom and W′ to whichthey are bound respectively, are joined to form a cycloalkyl,cycloalkenyl or heterocyclic group having at least five atoms in thecycloalkyl, cycloalkenyl or heterocyclic group and optionally containingor additionally containing in the case of the heterocyclic group 1 to 3heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur, and wherein the heterocyclic group is mono-cyclic;

and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl orheterocyclic group of formula Ia or Ib is optionally substituted, on anyring atom capable of substitution, with 1-3 substituents selected fromthe group consisting of alkyl, substituted alkyl, alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substitutedamino, amidino, alkyl amidino, thioamidino, aminoacyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl,substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substitutedaryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where each R isindependently hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substitutedalkyl, —NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, —N[S(O)₂—R′]₂ and —N[S(O)₂—NR′]₂ where each R′ isindependently selected from the group consisting of alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic;

R³ and R^(3′) are independently selected from the group consisting ofhydrogen, isopropyl, —CH₂Z where Z is selected from the group consistingof hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl,aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl,substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic, and

where R³ and R^(3′) are joined to form a substituent selected from thegroup consisting of ═CHZ where Z is defined above provided that Z is nothydroxyl or thiol, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, heterocyclic and substituted heterocyclic;

Q is selected from the group consisting of —O—, —S—, —S(O)—, —S(O)₂, and—NR⁴—;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic or, optionally, R⁴ and R¹ or R⁴ and R², together with theatoms to which they are bound, are joined to form a heteroaryl, asubstituted heteroaryl, a heterocyclic or a substituted heterocyclicgroup;

W is selected from the group consisting of nitrogen and carbon; and

W′ is selected from the group consisting of nitrogen, carbon, oxygen,sulfur, S(O), and S(O)₂;

X is selected from the group consisting of hydroxyl, alkoxy, substitutedalkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substitutedcycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy,substituted aryloxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy and —NR″R″ where each R″ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof;

and further wherein the compound of formula Ia and/or Ib has a bindingaffinity to VLA-4 as expressed by an IC₅₀ of about 15 μM or less.

Preferably, in the above method, R³ is —(CH₂)_(x)—Ar—R⁹, where Ar isaryl, substituted aryl, heteroaryl and substituted heteroaryl; R⁹ isselected from the group consisting of acyl, acylamino, acyloxy,aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,oxythiocarbonylamino, thioamidino, thiocarbonylamino,aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylaminoand oxysulfonyl; and x is an integer from 0 to 4. R^(3′) is preferablyalkyl or hydrogen; more preferably, R^(3′) is hydrogen.

More preferably, R³ is a group of the formula:

wherein R⁹ and x are as defined herein. Preferably, R⁹ is in the paraposition of the phenyl ring; and x is an integer of from 1 to 4, morepreferably, x is 1.

In a preferred embodiment, R⁹ is selected from —O—Z—NR¹¹R^(11′) and—O—Z—R¹² wherein R¹¹ and R^(11′) are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, substituted heterocyclic, and where R¹¹ and R^(11′) arejoined to form a heterocycle or a substituted heterocycle, R¹² isselected from the group consisting of heterocycle and substitutedheterocycle, and Z is selected from the group) consisting of —C(O)— and—SO₂—. More preferably, R⁹ is —OC(O)NR¹¹R^(11′), wherein R¹¹ and R^(11′)are as defined herein.

In the above method, Z is preferably —C(O)—. Preferably, Q is —NR⁴—.

In a preferred embodiment, the above method employs a compound offormula IIa or IIb:

wherein R³, R^(3′) and X are as defined herein;

ring A and ring B independently form a heteroaryl or substitutedheteroaryl group having two nitrogen atoms in the heteroaryl ring;

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, substituted heterocylic, heteroaryl and substitutedheteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, and —SO₂R¹⁰ where R¹⁰ isselected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl;

or optionally, one of, R⁴ and ring A, R⁴ and R⁵, R⁴ and R⁶, or R⁵ andR⁶, together with the atoms to which they are bound, can be joined toform a heterocyclic or substituted heterocyclic ring;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof; and provided that ring B does not form a 6-amino or substitutedamino pyrimidin-4-yl group.

Preferably, ring A forms a pyridazine, pyrimidine or pyrazine ring; morepreferably, a pyrimidine or pyrazine ring; wherein the pyridazine,pyrimidine or pyrazine ring is optionally substituted with 1 to 3substituents selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and halogen.

Preferably, ring B forms a pyridazine, pyrimidine, pyrazine,1-oxo-1,2,5-thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring; morepreferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or a1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine orpyrazine ring is optionally substituted with 1 to 3 substituentsselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen.

In another preferred embodiment, the method employs a compound offormula Ma, IIIc, IIId, IIIe or IIIf:

wherein R³, R^(3′) and X are as defined herein;

R^(4′) is selected from the group consisting of hydrogen and alkyl or,optionally, one of, R^(4′) and R⁵, R^(4′) and R⁶, R⁵ and R⁶, R⁵ and R⁸,or R⁶ and R⁸, together with the atoms to which they are bound, arejoined to form a heterocyclic, a substituted heterocyclic, a heteroarylor substituted heteroaryl group optionally containing from 1 to 3additional hetero ring atoms selected from the group consisting ofoxygen, nitrogen and sulfur;

R^(4′) is selected from the group consisting of hydrogen and alkyl;

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, substituted heterocylic, heteroaryl and substitutedheteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, and —SO₂R¹⁰ where R¹⁰ isselected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R¹⁶ and R¹⁷ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and halogen; and

R¹⁸ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic;

R²⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R²¹ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heterocyclic andsubstituted heterocyclic;

b is 1 or 2;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.

Preferably, the method employs a compound of formula IIId, IIIe or IIIf.

In another of its method aspects, this invention is directed to a methodfor treating a disease mediated by VLA-4 in a patient, which methodcomprises administering a pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of formula IVa and/or IVb:

wherein, in formula IVa, R¹ and R², together with the carbon atom and Wto which they are bound respectively, are joined to form an aryl,cycloalkenyl, heteroaryl or heterocyclic group having at least fiveatoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group andoptionally containing or additionally containing in the case ofheteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur, and wherein theheteroaryl or heterocyclic group is mono-cyclic;

in formula IVb, R¹ and R², together with the carbon atom and W′ to whichthey are bound respectively, are joined to form a cycloalkyl,cycloalkenyl or heterocyclic group having at least five atoms in thecycloalkyl, cycloalkenyl or heterocyclic group and optionally containingor additionally containing in the case the heterocyclic group 1 to 3heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur, and wherein the heterocyclic group is mono-cyclic;

and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl orheterocyclic group of formula IVa or IVb is optionally substituted, onany ring atom capable of substitution, with 1-3 substituents selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl,substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substitutedaryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where each R isindependently hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substitutedalkyl, —NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, —N[S(O)₂—R′]₂ and —N[S(O)₂—NR′]₂ where each R′ isindependently selected from the group consisting of alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic;

R¹³ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl, Cy,and Cy-C₁₋₁₀ alkyl, wherein alkyl is optionally substituted with one tofour substituents independently selected from R^(a); and Cy isoptionally substituted with one to four substituents independentlyselected from R^(b);

R¹⁴ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, Cy, Cy-C₁₋₁₀ alkyl, Cy-C₂₋₁₀ alkenyl andCy-C₂₋₁₀ alkynyl, wherein alkyl, alkenyl, and alkynyl are optionallysubstituted with one to four substituents selected from phenyl andR^(x), and Cy is optionally substituted with one to four substituentsindependently selected from R^(γ);

or R¹³, R¹⁴ and the atoms to which they are attached together form amono- or bicyclic ring containing 0-2 additional heteroatoms selectedfrom N, O and S;

R¹⁵ is selected from the group consisting of C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, aryl, aryl-C₁₋₁₀ alkyl, heteroaryl, heteroaryl-C₁₋₁₀alkyl, wherein alkyl, alkenyl and alkynyl are optionally substitutedwith one to four substituents selected from R^(x), and aryl andheteroaryl are optionally substituted with one to four substituentsindependently selected from R^(y);

or R¹⁴, R¹⁵ and the carbon to which they are attached form a 3-7membered mono- or bicyclic ring containing 0-2 heteroatoms selected fromN, O and S;

R^(a) is selected from the group consisting of Cy and a group selectedfrom R^(x), wherein Cy is optionally substituted with one to foursubstituents independently selected from R^(c);

R^(b) is selected from the group consisting of R^(a), C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, aryl C₁₋₁₀alkyl, heteroaryl C₁₋₁₀ alkyl, whereinalkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substitutedwith a group independently selected from R^(c);

R^(c) is selected from the group consisting of halogen, NO₂, C(O)OR^(f),C₁₋₄ alkyl, C₁₋₄ alkoxy, aryl, aryl C₁₋₄ alkyl, aryloxy, heteroaryl,NR^(f)R^(g), R^(f)C(O)R^(g), NR^(f)C(O)NR^(f)R^(g), and CN;

R^(d) and R^(e) are independently selected from hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, Cy and Cy C₁₋₁₀alkyl, wherein alkyl,alkenyl, alkynyl and Cy are optionally substituted with one to foursubstituents independently selected from R^(c);

or R^(d) and R^(e) together with the atoms to which they are attachedform a heterocyclic ring of 5 to 7 members containing 0-2 additionalheteroatoms independently selected from oxygen, sulfur and nitrogen;

R^(f) and R^(g) are independently selected from hydrogen, C₁₋₁₀ alkyl,Cy and Cy-C₁₋₁₀ alkyl wherein Cy is optionally substituted with C₁₋₁₀alkyl; or R^(f) and R^(g) together with the carbon to which they areattached form a ring of 5 to 7 members containing 0-2 heteroatomsindependently selected from oxygen, sulfur and nitrogen;

R^(h) is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cyano, aryl, aryl C₁₋₁₀ alkyl, heteroaryl,heteroaryl C₁₋₁₀ alkyl, and —SO₂R^(i); wherein alkyl, alkenyl, andalkynl are optionally substituted with one to four substitutentsindependently selected from R^(a); and aryl and heteroaryl are eachoptionally substituted with one to four substituents independentlyselected from R^(b);

R^(i) is selected from the group consisting of C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl andaryl are each optionally substituted with one to four substituentsindependently selected from R^(c);

R^(x) is selected from the group consisting of —OR^(d), —NO₂, halogen,—S(O)_(m)R^(d), —SR^(d), —S(O)₂OR^(d), —S(O)_(m)NR^(d)R^(e),—NR^(d)R^(e), —O(CR^(f)R^(g))_(n)NR^(d)R^(e), —C(O)R^(d), —CO₂R^(d),—CO₂(CR^(f)R^(g))_(n)CONR^(d)R^(e), —OC(O)R^(d), —CN, —C(O)NR^(d)R^(e),—NR^(d)C(O)R^(e), —OC(O)NR^(d)R^(e), —NR^(d)C(O)OR^(e),—NR^(d)C(O)NR^(d)R^(e), —CR^(d)(N—OR^(e)), CF₃, oxo,NR^(d)C(O)NR^(d)SO₂R^(i), NR^(d)S(O)_(m)R^(e), —OS(O)₂OR^(d), andOP(O)(OR^(d))₂;

R^(y) is selected from the group consisting of R^(x), C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, aryl C₁₋₁₀alkyl, heteroaryl C₁₋₁₀ alkyl,cycloalkyl, heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl areeach optionally substituted with one to four substitutents independentlyselected from R^(x);

Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is an integer from 1 to 2;

n is an integer from 1 to 10;

W is selected from the group consisting of carbon and nitrogen;

W′ is selected from the group consisting of carbon, nitrogen, oxygen,sulfur, S(O) and S(O)₂;

X′ is selected from the group consisting of —C(O)OR^(d),—P(O)(OR^(d))(OR^(e)), —P(O)(R^(d))(OR^(e)), —S(O)_(m)OR^(d),—C(O)NR^(d)R^(h), and -5-tetrazolyl;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof;

and further wherein the compound of formula IVa and/or IVb has a bindingaffinity to VLA-4 as expressed by an IC₅₀ of about 15 μM or less.

Preferably, in the above method, R¹ and R², together with the carbonatom and W to which they are bound respectively, are joined to form aheteroaryl or substituted heteroaryl group having two nitrogen atoms inthe heteroaryl ring. Optionally, the heteroaryl ring may contain otherheteroatoms such as oxygen or sulfur. More preferably, R¹ and R²,together with the carbon atom and W to which they are boundrespectively, are joined to form a pyridazine, pyrimidine, pyrazine,1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; morepreferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine,pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring isoptionally substituted with 1 to 3 substituents selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic and halogen.

Preferably, X′ is —C(O)OR^(d).

In a preferred embodiment, the above method employs a compound offormula Va, Vc, Vd, Ve or Vf:

wherein R¹³, R¹⁴, R¹⁵ and X′ are as defined herein;

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, substituted heterocylic, heteroaryl and substitutedheteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, and —SO₂R¹⁰ where R¹⁰ isselected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl; and

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R¹⁶ and R¹⁷ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and halogen; and

R¹⁸ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic;

R²⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R²¹ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heterocyclic andsubstituted heterocyclic;

b is 1 or 2;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.

More preferably, the above method employs a compound of formula Vd, Veor Vf.

In yet another of its method aspects, this invention is directed to amethod for treating a disease mediated by VLA-4 in a patient, whichmethod comprises administering a pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of formula VIa and/or VIb:

wherein, in formula VIa, R¹ and R², together with the carbon atom and Wto which they are bound respectively, are joined to form an aryl,cycloalkenyl, heteroaryl or heterocyclic group having at least fiveatoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group andoptionally containing or additionally containing in the case ofheteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur, and wherein theheteroaryl or heterocyclic group is mono-cyclic;

in formula VIb, R¹ and R², together with the carbon atom and W′ to whichthey are bound respectively, are joined to form a cycloalkyl,cycloalkenyl or heterocyclic group having at least five atoms in thecycloalkyl, cycloalkenyl or heterocyclic group and optionally containingor additionally containing in the case of the heterocyclic group 1 to 3heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur, and wherein the heterocyclic group is mono-cyclic;

and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl orheterocyclic group of formula VIa or VIb is optionally substituted, onany ring atom capable of substitution, with 1-3 substituents selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl,substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substitutedaryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl, heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereeach R is independently hydrogen or alkyl, —NRS(O)₂-alkyl,—NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl, —NRS(O)₂-substituted aryl,—NRS(O)₂-heteroaryl, —NRS(O)₂-substituted heteroaryl,—NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O), —NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl,—N[S(O)₂—R′]₂ and —N[S(O)₂—NR′]₂ where each R′ is independently selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic;

R²³ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyloptionally substituted with one to four substituents independentlyselected from R^(a′) and Cy optionally substituted with one to foursubstituents independently selected from R^(b′);

R²⁴ is selected from the group consisting of Ar¹—Ar²—C₁₋₁₀ alkyl,Ar¹—Ar²—C₂₋₁₀ alkenyl, Ar¹—Ar²—C₂₋₁₀ alkynyl, wherein Ar¹ and Ar² areindependently aryl or heteroaryl each of which is optionally substitutedwith one to four substituents independently selected from R^(b′); alkyl,alkenyl and alkynyl are optionally substituted with one to foursubstituents independently selected from R^(a′);

R²⁵ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl, andheteroaryl C₁₋₁₀ alkyl, wherein alkyl, alkenyl and alkynyl areoptionally substituted with one to four substituents selected fromR^(a′), and aryl and heteroaryl are optionally substituted with one tofour substituents independently selected from R^(b′);

R^(a′) is selected from the group consisting of Cy, —OR^(d′), —NO₂,halogen —S(O)_(m)R^(d′), —SR^(d′), —S(O)₂OR^(d′),—S(O)_(m)NR^(d′)R^(e′), —NR^(d)R^(e′),—O(CR^(f)R^(g′))_(n)NR^(d′)R^(e′), —C(O)R^(d′), —CO₂R^(d′),—CO₂(CR^(f′)R^(g′))_(n)CONR^(d′)R^(e′), —OC(O)R^(d′), —CN,—C(O)NR^(d′)R^(e′), —NR^(d′)C(O)R^(e′), —OC(O)NR^(d′)R^(e′),—NR^(d′)C(O)OR^(e′), —NR^(d′)C(O)NR^(d′)R^(e′), —CR^(d′)(N—OR^(e′)),CF₃, and —OCF₃;

wherein Cy is optionally substituted with one to four substituentsindependently selected from R^(c′);

R^(b′) is selected from the group consisting of R^(a′), C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl C₁₋₁₀ alkyl, heteroaryl C₁₋₁₀alkyl,

wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted witha group independently selected from R^(c′);

R^(c′) is selected from the group consisting of halogen, amino, carboxy,C₁₋₄ alkyl, C₁₋₄ alkoxy, aryl, aryl C₁₋₄-alkyl, hydroxy, CF₃, andaryloxy;

R^(d′) and R^(e′) are independently selected from hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, Cy and Cy C₁₋₁₀alkyl, wherein alkyl,alkenyl, alkynyl and Cy are optionally substituted with one to foursubstituents independently selected from R^(c′); or R^(d′) and R^(e′)together with the atoms to which they are attached form a heterocyclicring of 5 to 7 members containing 0-2 additional heteroatomsindependently selected from oxygen, sulfur and nitrogen;

R^(f′) and R^(g′) are independently selected from hydrogen, C₁₋₁₀ alkyl,Cy and Cy-C₁₋₁₀ alkyl; or R^(f′) and R^(g′) together with the carbon towhich they are attached form a ring of 5 to 7 members containing 0-2heteroatoms independently selected from oxygen, sulfur and nitrogen;

R^(h′) is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cyano, aryl, aryl C₁₋₁₀ alkyl, heteroaryl,heteroaryl C₁₋₁₀ alkyl, or —SO₂R^(i′);

wherein alkyl, alkenyl, and alkynyl are optionally substituted with oneto four substitutents independently selected from R^(a′); and aryl andheteroaryl are each optionally substituted with one to four substituentsindependently selected from R^(b′);

R^(i′) is selected from the group consisting of C₁₋₁₀ alkyl-, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, and aryl;

wherein alkyl, alkenyl, alkynyl and aryl are each optionally substitutedwith one to four substituents independently selected from R^(c′);

Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;

X″ is selected from the group consisting of —C(O)OR^(d′),—P(O)(OR^(d′))(OR^(e′)), —P(O)(R^(d′))(OR^(e′)), —S(O)_(m)OR^(d′),—C(O)NR^(d′)R^(h′), and -5-tetrazolyl;

m is an integer from 1 to 2;

n is an integer from 1 to 10;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof;

and further wherein the compound of formula VIa and/or VIb has a bindingaffinity to VLA-4 as expressed by an IC₅₀ of about 15 μM or less.

Preferably, in the above method, R¹ and R², together with the carbonatom and W to which they are bound respectively, are joined to form aheteroaryl or substituted heteroaryl group having two nitrogen atoms inthe heteroaryl ring. Optionally, the heteroaryl ring may contain otherheteroatoms such as oxygen or sulfur. More preferably, R¹ and R²,together with the carbon atom and W to which they are boundrespectively, are joined to form a pyridazine, pyrimidine, pyrazine,1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole, ring; morepreferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine,pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring,is optionally substituted with 1 to 3 substituents selected from thegroup consisting of alkyl, substituted alkyl, alkoxy, substitutedalkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen.

Preferably, in the above method, X″ is —C(O)OR^(d′).

Preferably, R²⁴ is —CH₂—Ar²—Ar¹ and R²⁵ is hydrogen.

In a preferred embodiment, the above method employs a compound offormula VIIa, VIIc, VIId, VIIe or VIIf:

wherein R²³, R²⁴, R²⁵ and X″ are as defined herein;

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, substituted heterocylic, heteroaryl and substitutedheteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, and —SO₂R¹⁰ where R¹⁰ isselected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl; and

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R¹⁶ and R¹⁷ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl; heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and halogen; and

R¹⁸ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic;

R²⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R²¹ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heterocyclic andsubstituted heterocyclic;

b is 1 or 2;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.

Preferably, the compound employed in the above method is selected fromformula VIIId, VIIe or VIIf.

The compounds and pharmaceutical compositions of this invention areuseful for treating disease conditions mediated by VLA-4 or leucocyteadhesion. Such disease conditions include, by way of example, asthma,Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (includingacute juvenile onset diabetes), inflammatory bowel disease (includingulcerative colitis and Crohn's disease), multiple sclerosis; rheumatoidarthritis, tissue transplantation, tumor metastasis, meningitis,encephalitis, stroke, and other cerebral traumas, nephritis, retinitis,atopic dermatitis, psoriasis, myocardial ischemia and acuteleukocyte-mediated lung injury such as that which occurs in adultrespiratory distress syndrome.

Other disease conditions include, but are not limited to, inflammatoryconditions such as erythema nodosum, allergic conjunctivitis, opticneuritis, uveitis, allergic rhinitis, Ankylosing spondylitis, psoriaticarthritis, vasculitis, Reiter's syndrome, systemic lupus erythematosus,progressive systemic sclerosis, polymyositis, dermatomyositis, Wegner'sgranulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporalarteritis, pericarditis, myocarditis, congestive heart failure,polyarteritis nodosa, hypersensitivity syndromes, allergy,hypereosinophilic syndromes, Churg-Strauss syndrome, chronic obstructivepulmonary disease, hypersensitivity pneumonitis, chronic activehepatitis, interstitial cystitis, autoimmune endocrine failure, primarybiliary cirrhosis, autoimmune aplastic anemia, chronic persistenthepatitis and thyroiditis.

In a preferred, embodiment, the disease condition mediated by VLA-4 isan inflammatory disease.

The present invention is also directed to novel compounds useful fortreating a disease condition mediated by VLA-4 or leucocyte adhesion.Accordingly, in one of its composition aspects, this invention isdirected to a compound of formula Ia and/or Ib:

wherein, in formula Ia, R¹ and R², together with the carbon atom and Wto which they are bound respectively, are joined to form an aryl,cycloalkenyl, heteroaryl or heterocyclic group having at least fiveatoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group andoptionally containing or additionally containing in the case ofheteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur, and wherein theheteroaryl or heterocyclic group is mono-cyclic;

in formula Ib, R¹ and R², together with the carbon atom and W′ to whichthey are bound respectively, are joined to form a cycloalkyl,cycloalkenyl or heterocyclic group having at least five atoms in thecycloalkyl, cycloalkenyl or heterocyclic group and optionally containingor additionally containing in the case of the heterocyclic group 1 to 3heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur, and wherein the heterocyclic group is mono-cyclic;

and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl orheterocyclic group of formula Ia or Ib is optionally substituted, on anyring atom capable of substitution, with 1-3 substituents selected fromthe group consisting of alkyl, substituted alkyl, alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substitutedamino, amidino, alkyl amidino, thioamidino, aminoacyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl,substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substitutedaryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where each R isindependently hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substitutedalkyl, —NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O), —NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O),—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substitutedheteroaryl, —NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substitutedheterocyclic where R is hydrogen or alkyl, —N[S(O)₂—R′]₂ and—N[S(O)₂—NR′]₂ where each R′ is independently selected from the groupconsisting of alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic;

R³ is —(CH₂)_(x)—Ar—R⁹, where Ar is aryl, substituted aryl, heteroaryland substituted heteroaryl; R⁹ is selected from the group consisting ofacyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino,oxythiocarbonylamino, thioamidino, thiocarbonylamino,aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylaminoand oxysulfonyl; x is an integer from 0 to 4;

R^(3′) is selected from the group consisting of hydrogen, isopropyl,—CH₂Z where Z is selected from the group consisting of hydrogen,hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl,substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic;

Q is selected from the group consisting of —O—, —S—, —S(O)—, —S(O)₂, and—NR⁴—;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic or, optionally, R⁴ and R¹ or R⁴ and R², together with theatoms to which they are bound, are joined to form a heteroaryl, asubstituted heteroaryl, a heterocyclic or a substituted heterocyclicgroup;

W is selected from the group consisting of nitrogen and carbon; and

W′ is selected from the group consisting of nitrogen, carbon, oxygen,sulfur, S(O), and S(O)₂;

X is selected from the group consisting of hydroxyl, alkoxy, substitutedalkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substitutedcycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy,substituted aryloxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy and —NR″R″ where each R″ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic;

and enantiomers, diasteromers and pharmaceutically acceptable saltsthereof;

and further wherein the compound of formula Ia and/or Ib has a bindingaffinity to VLA-4 as expressed by an IC₅₀ of about 15 μM or less.

More preferably, R³ is a group of the formula:

wherein R⁹ and x are as defined herein. Preferably, R⁹ is in the paraposition of the phenyl ring; and x is an integer of from 1 to 4, morepreferably, x is 1.

Preferably, R^(3′) is hydrogen.

In a preferred embodiment, R⁹ is selected from the group consisting of—O—Z—NR¹¹R^(11′) and —O—Z—R¹² wherein R¹¹ and R^(11′) are independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, and where R¹¹ andR^(11′) are joined to form a heterocycle or a substituted heterocycle,R¹² is selected from the group consisting of heterocycle and substitutedheterocycle, and Z is selected from the group consisting of —C(O)— and—SO₂—. More preferably, R⁹ is —OC(O)NR¹¹R^(11′), wherein R¹¹ and R^(11′)are as defined herein.

Preferably, in the above compounds, Z is —C(O)— and Q is preferably—NR⁴—.

In a preferred embodiment, this invention is directed to compounds offormula IIa or IIb:

wherein X is as defined herein;

R³ is —(CH₂)_(x)—Ar—R⁹, where Ar is aryl, substituted aryl, heteroaryland substituted heteroaryl; R⁹ is selected from the group consisting ofacyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino,oxythiocarbonylamino, thioamidino, thiocarbonylamino,aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylaminoand oxysulfonyl; x is an integer from 0 to 4;

R^(3′) is selected from the group consisting of hydrogen, isopropyl,—CH₂Z where Z is selected from the group consisting of hydrogen,hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl,substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic;

ring A and ring B independently form a heteroaryl or substitutedheteroaryl group having two nitrogen atoms in the heteroaryl ring;

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, substituted heterocylic, heteroaryl and substitutedheteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, and —SO₂R¹⁰ where R¹⁰ isselected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl;

or optionally, one of, R⁴ and ring A, R⁴ and R⁵, R⁴ and R⁶, or R⁵ andR⁶, together with the atoms to which they are bound, can be joined toform a heterocyclic or substituted heterocyclic ring;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof; and provided that ring B does not form a 6-amino or substitutedamino pyrimidin-4-yl group.

R^(3′) is preferably hydrogen. Preferably, x is an integer from 1 to 4;more preferably, x is 1.

Preferably, ring A forms a pyridazine, pyrimidine or pyrazine ring; morepreferably, a pyrimidine or pyrazine ring; wherein the pyridazine,pyrimidine or pyrazine ring is optionally substituted with 1 to 3substituents selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and halogen.

Preferably, ring B forms a pyridazine, pyrimidine, pyrazine,1-oxo-1,2,5-thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring; morepreferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or a1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine orpyrazine ring is optionally substituted with 1 to 3 substituentsselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen.

In another preferred embodiment, this invention is directed to compoundsof formula IIIa, IIIc, IIId, IIIe or IIIf:

wherein X is as defined herein;

R³ is —(CH₂)_(x)—Ar—R⁹, where Ar is aryl, substituted aryl, heteroaryland substituted heteroaryl; R⁹ is selected from the group consisting ofacyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino,oxythiocarbonylamino, thioamidino, thiocarbonylamino,aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylaminoand oxysulfonyl; x is an integer from 0 to 4;

R^(3′) is selected from the group consisting of hydrogen, isopropyl,—CH₂Z where Z is selected from the group consisting of hydrogen,hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl,substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic;

R^(4′) is selected from the group consisting of hydrogen and, alkyl or,optionally; one of, R^(4′) and R⁵, R^(4′) and R⁶, R⁵ and R⁶, R⁵ and R⁸,or R⁶ and R⁸, together with the atoms to which they are bound, arejoined to form a heterocyclic, a substituted heterocyclic, a heteroarylor substituted heteroaryl group optionally containing from 1 to 3additional hetero ring atoms selected from the group consisting ofoxygen, nitrogen and sulfur;

R^(4′) is selected from the group consisting of hydrogen and alkyl;

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, substituted heterocylic, heteroaryl and substitutedheteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, and —SO₂R¹⁰ where R¹⁰ isselected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R¹⁶ and R¹⁷ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and halogen; and

R¹⁸ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic;

R²⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R²¹ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl; heterocyclic andsubstituted heterocyclic;

b is 1 or 2;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.

In the above compounds, R^(3′) is preferably hydrogen. Preferably, x isan integer from 1 to 4; more preferably, x is 1.

Preferably, the compound is selected from formula IIId, IIIe or IIf.

In another of its composition aspects, this invention is directed to acompound of formula IVa:

wherein R¹ and R², together with the carbon atom and W to which they arebound respectively, are joined to form a heteroaryl group having twonitrogen atoms in the heteroaryl ring;

and further wherein said heteroaryl group is optionally substituted, onany ring atom capable of substitution, with 1-3 substituents selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl,substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substitutedaryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where each R isindependently hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substitutedalkyl, —NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl, —NRS(O),—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substituted aryl,—NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, —N[S(O)₂—R′]₂ and —N[S(O)₂—NR′]₂ where each R′ isindependently selected from the group consisting of alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic;

R¹³ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl, Cy,and Cy-C₁₋₁₀ alkyl, wherein alkyl is optionally substituted with one tofour substituents independently selected from R^(a); and Cy isoptionally substituted with one to four substituents independentlyselected from R^(b);

R¹⁴ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, Cy, Cy-C₁₋₁₀ alkyl, Cy-C₂₋₁₀ alkenyl andCy-C₂₋₁₀ alkynyl, wherein alkyl, alkenyl, and alkynyl are optionallysubstituted with one to four substituents selected from phenyl andR^(X), and Cy is optionally substituted with one to four substituentsindependently selected from R^(y);

or R¹³, R¹⁴ and the atoms to which they are attached together form amono- or bicyclic ring containing 0-2 additional heteroatoms selectedfrom N, O and S;

R¹⁵ is selected from the group consisting of C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, aryl, aryl-C₁₋₁₀ alkyl, heteroaryl, heteroaryl-C₁₋₁₀alkyl, wherein alkyl, alkenyl and alkynyl are optionally substitutedwith one to four substituents selected from R^(x), and aryl andheteroaryl are optionally substituted with one to four substituentsindependently selected from R^(y);

or R¹⁴, R¹⁵ and the carbon to which they are attached form a 3-7membered mono- or bicyclic ring containing 0-2 heteroatoms selected fromN, O and S;

R^(a) is selected from the group consisting of Cy and a group selectedfrom R^(x), wherein Cy is optionally substituted with one to foursubstituents independently selected from R^(c);

R^(b) is selected from the group consisting of R^(a), C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, aryl C₁₋₁₀alkyl, heteroaryl C₁₋₁₀ alkyl, whereinalkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substitutedwith a group independently selected from R^(c);

R^(c) is selected from the group consisting of halogen, NO₂, C(O)OR^(f),C₁₋₄ alkyl, C₁₋₄ alkoxy, aryl, aryl C₁₋₄ alkyl, aryloxy, heteroaryl,NR^(f)R^(g), R^(f)C(O)R^(g), NR^(f)C(O)NR^(f)R^(g), and CN;

R^(d) and R^(e) are independently selected from hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, Cy and Cy C₁₋₁₀alkyl, wherein alkyl,alkenyl, alkynyl and Cy are optionally substituted with one to foursubstituents independently, selected from R^(c);

or R^(d) and R^(e) together with the atoms to which they are attachedform a heterocyclic ring of 5 to 7 members containing 0-2 additionalheteroatoms independently selected from oxygen, sulfur and nitrogen;

R^(f) and R^(g) are independently selected from hydrogen, C₁₋₁₀ alkyl,Cy and Cy-C₁₋₁₀ alkyl wherein Cy is optionally substituted with C₁₋₁₀alkyl; or R^(f) and R^(g) together with the carbon to which they areattached form a ring of 5 to 7 members containing 0-2 heteroatomsindependently selected from oxygen, sulfur and nitrogen;

R^(h) is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cyano, aryl, aryl C₁₋₁₀ alkyl, heteroaryl,heteroaryl C₁₋₁₀ alkyl, and —SO₂R^(i); wherein alkyl, alkenyl, andalkynl are optionally substituted with one to four substitutentsindependently selected from R^(a); and aryl and heteroaryl are eachoptionally substituted with one to four substituents independentlyselected from R^(b);

R^(i) is selected from the group consisting of C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl andaryl are each optionally substituted with one to four substituentsindependently selected from R^(c);

R^(x) is selected from the group consisting of —OR^(d), —NO₂, halogen,—S(O)_(m)R^(d), —SR^(d), —S(O)₂OR^(d), —S(O)_(m)NR^(d)R^(e),—NR^(d)R^(e), —O(CR^(f)R^(g))_(n)NR^(d)R^(e), —C(O)R^(d), —CO₂R^(d),—CO₂(CR^(f)R^(g))_(n)CONR^(d)R^(e), —OC(O)R^(d), —CN, —C(O)NR^(d)R^(e),—NR^(d)C(O)R^(e), —OC(O)NR^(d)″R^(e), —NR^(d)″C(O)OR^(e),—NR^(d)C(O)NR^(d)R^(e), —CR^(d)(N—OR^(e)), CF₃, oxo,NR^(d)C(O)NR^(d)SO₂R^(i), NR^(d)S(O)_(m)R^(e), —OS(O)₂OR^(d), and—OP(O)(OR^(d))₂;

R^(y) is selected from the group consisting of R^(x), C₁₋₁₀ alkyl, C₁₋₁₀alkenyl, C₂₋₁₀ alkynyl, aryl C₁₋₁₀alkyl, heteroaryl C₁₋₁₀ alkyl,cycloalkyl, heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl areeach optionally substituted with one to four substitutents independentlyselected from R^(x);

Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is an integer from 1 to 2;

n is an integer from 1 to 10;

W is selected from the group consisting of carbon and nitrogen;

W′ is selected from the group consisting of carbon, nitrogen, oxygen,sulfur, S(O) and S(O)₂;

X′ is selected from the group consisting of —C(O)OR^(d),—P(O)(OR^(d))(OR^(e)), —P(O)(R^(d))(OR^(e)), —S(O)_(m)OR^(d),—C(O)NR^(d)R^(h), and -5-tetrazolyl;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof;

and further wherein the compound of formula IV has a binding affinity toVLA-4 as expressed by an IC₅₀ of about 15 μM or less;

and provided that when R¹ and R², together with the carbon atom and W towhich they are bound respectively, are joined to form a2-arylpyrimidin-4-yl group and R¹⁴ is hydrogen, then R¹⁵ is not alkyl offrom 1 to 6 carbon atoms optionally substituted with hydroxyl; and whenR¹ and R², together with the carbon atom and W to which they are boundrespectively, are joined to form a 5-arylpyrazin-2-yl group and R¹⁴ ishydrogen, then R¹⁵ is not 4-hydroxybenzyl.

In the above compounds, R¹ and R² are preferably joined to form artpyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or1,1-dioxo-1,2,5-thiadiazole ring; more preferably, a pyrimidine,pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring;wherein the pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3substituents selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and halogen.

Preferably, in the above compounds, X′ is —C(O)OR^(d).

In a preferred embodiment, this invention is directed to compounds offormula Va, Vc, Vd, Ve or Vf:

wherein R¹³, R¹⁴, R¹⁵ and X′ are as defined herein;

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, substituted heterocylic, heteroaryl and substitutedheteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, and —SO₂R¹⁰ where R¹⁰ isselected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl; and

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R¹⁶ and R¹⁷ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and halogen; and

R¹⁸ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic;

R²⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R²¹ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heterocyclic andsubstituted heterocyclic;

b is 1 or 2;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.

More preferably, the compound is selected from formula Vd, Ve or Vf.

In yet another of its composition aspects, this invention is directed toa compound of formula VIa and/or VIb:

wherein, in formula VIa, R¹ and R², together with the carbon atom and Wto which they are bound respectively, are joined to form an aryl,cycloalkenyl, heteroaryl or heterocyclic group having at least fiveatoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group andoptionally containing or additionally containing in the case ofheteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur, and wherein theheteroaryl or heterocyclic group is mono-cyclic;

in formula VIb, R¹ and R², together with the carbon, atom and W′ towhich they are bound respectively, are joined to form a cycloalkyl,cycloalkenyl or heterocyclic group having at least five atoms in thecycloalkyl, cycloalkenyl or heterocyclic group and optionallycontaining, or additionally containing in the case of the heterocyclicgroup 1 to 3 heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;

and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl orheterocyclic group of formula VIa or VIb is optionally substituted, onany ring atom capable of substitution, with 1-3 substituents selectedfrom the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl,aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl,substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substitutedaryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where each R isindependently hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substitutedalkyl, —NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, —N[S(O)₂—R′]₂ and —N[S(O)₂—NR′]₂ where each R′ isindependently selected from the group consisting of alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic;

R²³ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyloptionally substituted with one to four substituents independentlyselected from R^(a′) and Cy optionally substituted with one to foursubstituents independently selected from R^(b′);

R²⁴ is selected from the group consisting of Ar¹—Ar²—C₁₋₁₀ alkyl,Ar¹—Ar²—C₂₋₁₀ alkenyl, Ar¹—Ar²—C₂₋₁₀ alkynyl, wherein Ar¹ and Ar² areindependently aryl or heteroaryl each of which is optionally substitutedwith one to four substituents independently selected from R^(b′); alkyl,alkenyl and alkynyl are optionally substituted with one to foursubstituents independently selected from R^(a′);

R²⁵ is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, aryl C₁₋₁₀alkyl, heteroaryl, andheteroaryl C₁₋₁₀ alkyl, wherein alkyl, alkenyl and alkynyl areoptionally substituted with one to four substituents selected fromR^(a′), and aryl and heteroaryl are optionally substituted with one tofour substituents independently selected from R^(b′);

R^(a′) is selected from the group consisting of Cy, —OR^(d′), —NO₂,halogen —S(O)_(m)R^(d′), —SR^(d′), —S(O)₂OR^(d′),—S(O)_(m)NR^(d′)R^(e′), —NR^(d′)R_(e′),—O(CR^(f′)R^(g′))_(n)NR^(d′)R^(e′), —C(O)R^(d′), —CO₂R^(d′),—CO₂(CR^(f′)R^(g′))_(n)CONR^(d′)R^(e′), —OC(O)R^(d′), —CN,—C(O)NR^(d′)R^(e′), —NR^(d′)C(O)R^(e′), —OC(O)NR^(d′)R^(e′),—NR^(d′)C(O)OR^(e′), —Nr^(d′)C(O)NR^(d′)R^(e′), —CR^(d′)(N—OR^(e′)),CF₃, and —OCF₃;

wherein Cy is optionally substituted with one to four substituentsindependently selected from R^(c′);

R^(b′) is selected from the group consisting of R^(a′), C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl C₁₋₁₀ alkyl, heteroaryl C₁₋₁₀alkyl,

wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted witha group independently selected from R^(c′);

R^(c′) is selected from the group consisting of halogen, amino, carboxy,C₁₋₄ alkyl, C₁₋₄ alkoxy, aryl, aryl C₁₋₄-alkyl, hydroxy, CF₃, andaryloxy;

R^(d′) and R^(e′) are independently selected from hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, Cy and Cy C₁₋₁₀alkyl, wherein alkyl,alkenyl, alkynyl and Cy are optionally substituted with one to foursubstituents independently selected from R^(c′); or R^(d′) and R^(e′)together with the atoms to which they are attached form a heterocyclicring of 5 to 7 members containing 0-2 additional heteroatomsindependently selected from oxygen, sulfur and nitrogen;

R^(f′) and R^(g′) are independently selected from hydrogen, C₁₋₁₀ alkyl,Cy and Cy-C₁₋₁₀ alkyl; or R^(f′) and R^(g′) together with the carbon towhich they are attached form a ring of 5 to 7 members containing 0-2heteroatoms independently selected from oxygen, sulfur and nitrogen;

R^(h′) is selected from the group consisting of hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cyano, aryl, aryl C₁₋₁₀ alkyl, heteroaryl,heteroaryl C₁₋₁₀ alkyl, or —SO₂R^(i′);

wherein alkyl, alkenyl, and alkynyl are optionally substituted with oneto four substitutents independently selected from R^(a′); and aryl andheteroaryl are each optionally substituted with one to four substituentsindependently selected from R^(b′);

R^(i′) is selected from the group consisting of C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, alkynyl, and aryl;

wherein alkyl, alkenyl, alkynyl and aryl are each optionally substitutedwith one to four substituents independently selected from R^(c′);

Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;

X″ is selected from the group consisting of —C(O)OR^(d′),—P(O)(OR^(d′))(OR^(e′)), —P(O)(R^(d′))(OR^(e′)), —S(O)_(m)OR^(d′),—C(O)NR^(d′)R^(h′), and -5-tetrazolyl;

m is an integer from 1 to 2;

n is an integer from 1 to 10;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof;

and further wherein the compounds of formula VIa and/or VIb have abinding affinity to VLA-4 as expressed by an IC₅₀ of about 15 μM orless.

In the above compounds, R¹ and R² are preferably joined to form aheteroaryl or substituted heteroaryl group having two nitrogen atoms inthe heteroaryl ring. More preferably, R¹ and R² are joined to form apyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or1,1-dioxo-1,2,5-thiadiazole ring; more preferably, a pyrimidine,pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring;wherein the pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3substituents selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and halogen.

Preferably, X″ is —C(O)OR^(d′).

In the above compounds, R²⁴ is preferably —CH₂—Ar²—Ar¹ and R²⁵ ispreferably hydrogen.

In a preferred embodiment, this invention is directed to compounds offormula VIIa, VIIc, VIId, VIIe or VIIf:

wherein R²⁴, R²⁵ and X″ are as defined herein;

R⁵ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, substituted heterocylic, heteroaryl and substitutedheteroaryl;

R⁶ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, and —SO₂R¹⁰ where R¹⁰ isselected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substitutedaryl, heteroaryl, substituted heteroaryl; and

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R¹⁶ and R¹⁷ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and halogen; and

R¹⁸ is selected from the group consisting of alkyl, substituted alkyl,alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic;

R²⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

R²¹ is selected from the group consisting of alkyl, substituted alkyl;alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heterocyclic andsubstituted heterocyclic;

b is 1 or 2;

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.

Preferably, the compound is selected from formula VIId, VIIe or VIIf.

This invention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of the compounds defined herein.

In the above compounds, when X is other than —OH or pharmaceutical saltsthereof, X is preferably a substituent which will convert (e.g.,hydrolyze, metabolize, etc.) in vivo to a compound where X is —OH or asalt thereof. Accordingly, suitable X groups are any art recognizedpharmaceutically acceptable groups which will hydrolyze or otherwiseconvert in vivo to a hydroxyl group or a salt thereof including, by wayof example, esters (X is alkoxy, substituted alkoxy, cycloalkoxy,substituted cycloalkoxy, alkenoxy, substituted alkenoxy, cycloalkenoxy,substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy,substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy,and the like).

Unless otherwise defined, R³ and R¹⁵ in the above compounds arepreferably selected from all possible isomers arising by substitutionwith the following groups:

4-methylbenzyl,

4-hydroxybenzyl,

4-methoxybenzyl,

4-t-butoxybenzyl,

4-benzyloxybenzyl,

4-[φ-CH(CH₃)O-]benzyl,

4-[φ-CH(COOH)O-]benzyl,

4-[BocNHCH₂C(O)NH-]benzyl,

4-chlorobenzyl,

4-[NH₂CH₂C(O)NH-]benzyl,

4-carboxybenzyl,

4-[CbzNHCH₂CH₂NH-]benzyl,

3-hydroxy-4-(φ-OC(O)NH-)benzyl,

4-[HOOCCH₂CH₂C(O)NH-]benzyl,

benzyl,

4-[2′-carboxylphenoxy-]benzyl,

4-[φ-C(O)NH-]benzyl,

3-carboxybenzyl,

4-iodobenzyl,

4-hydroxy-3,5-diiodobenzyl,

4-hydroxy-3-iodobenzyl,

4-[2′-carboxyphenyl-]benzyl,

φ-CH₂CH₂—,

4-nitrobenzyl,

2-carboxybenzyl,

4-[dibenzylamino]-benzyl,

4-[(1′-cyclopropylpiperidin-4′-yl)C(O)NH-]benzyl,

4-[-NHC(O)CH₂NHBoc]benzyl,

4-carboxybenzyl,

4-hydroxy-3-nitrobenzyl,

4-[-NHC(O)CH(CH₃)NHBoc]benzyl,

4-[-NHC(O)CH(CH₂φ)NHBoc]benzyl,

isobutyl,

methyl,

4-[CH₃C(O)NH-]benzyl,

—CH₂-(3-indolyl),

n-butyl,

t-butyl-OC(O)CH₂—,

t-butyl-OC(O)CH₂CH₂—,

H₂NC(O)CH₂—,

H₂NC(O)CH₂CH₂—,

BocNH—(CH₂)₄—,

t-butyl-OC(O)—(CH₂)₂—,

HOOCCH₂—,

HOOC(CH₂)₂—,

H₂N(CH₂)₄—,

isopropyl,

(1-naphthyl)-CH₂—,

(2-naphthyl)-CH₂—,

(2-thiophenyl)-CH₂—,

(φ-CH₂—OC(O)NH—(CH₂)₄—,

cyclohexyl-CH₂—,

benzyloxy-CH₂—,

HOCH₂—,

5-(3-N-benzyl)imidazolyl-CH₂—,

2-pyridyl-CH₂—,

3-pyridyl-CH₂—,

4-pyridyl-CH₂—,

5-(3-N-methyl)imidazolyl-CH₂—,

N-benzylpiperid-4-yl-CH₂—,

N-Boc-piperidin-4-yl-CH₂—,

N-(phenyl-carbonyl)piperidin-4-yl-CH₂—,

H₃CSCH₂CH₂—,

1-N-benzylimidazol-4-yl-CH₂—,

iso-propyl-C(O)NH—(CH₂)₄—,

iso-butyl-C(O)NH—(CH₂)₄—,

phenyl-C(O)NH—(CH₂)₄—,

benzyl-C(O)NH—(CH₂)₄—,

allyl-C(O)NH—(CH₂)₄—,

4-(3-N-methylimidazolyl)-CH₂—,

4-imidazolyl,

4-[(CH₃)₂NCH₂CH₂CH₂—O-]benzyl,

4-[(benzyl)₂N-]-benzyl,

4-aminobenzyl,

allyloxy-C(O)NH(CH₂)₄—,

allyloxy-C(O)NH(CH₂)₃—,

allyloxy-C(O)NH(CH₂)₂—,

NH₂C(O)CH₂—,

φ-CH═,

2-pyridyl-C(O)NH—(CH₂)₄—,

4-methylpyrid-3-yl-C(O)NH—(CH₂)₄—,

3-methylthien-2-yl-C(O)NH—(CH₂)₄—,

2-pyrrolyl-C(O)NH—(CH₂)₄—,

2-furanyl-C(O)NH—(CH₂)₄—,

4-methylphenyl-SO₂—N(CH₃)CH₂C(O)NH(CH₂)₄—,

4-[cyclopentylacetylenyl]-benzyl,

4-[-NHC(O)—(N-Boc)-pyrrolidin-2-yl)]-benzyl-,

1-N-methylimidazol-4-yl-CH₂—,

imidazol-5-yl-CH₂—,

6-methylpyrid-3-yl-C(O)NH—(CH₂)₄—,

4-[2′-carboxymethylphenyl]-benzyl,

4-[-NHC(O)NHCH₂CH₂CH₂-φ]-benzyl,

4-[-NHC(O)NHCH₂CH₂-φ]-benzyl,

—CH₂C(O)NH(CH₂)₄φ,

4-[φ(CH₂)₄O-]-benzyl,

4-[-C≡C-φ-4′φ]-benzyl,

4-[-C≡C—CH₂—O—S(O)₂-4′-CH₃-φ]-benzyl,

4-[-C≡C—CH₂NHC(O)NH₂]-benzyl,

4-[-C≡C—CH₂—O-4′-COOCH₂CH₃-φ]-benzyl,

4-[-C≡C—CH(NH₂)-cyclohexyl]-benzyl,

—(CH₂)₄NHC(O)CH₂-3-indolyl,

—(CH₂)₄NHC(O)CH₂CH₂-3-indolyl,

—(CH₂)₄NHC(O)-3-(5-methoxyindolyl),

—(CH₂)₄NHC(O)-3-(1-methylindolyl),

—(CH₂)₄NHC(O)-4-(-SO₂(CH₃)-φ),

—(CH₂)₄NHC(O)-4-(C(O)CH₃)-phenyl,

—(CH₂)₄NHC(O)-4-fluorophenyl,

—(CH₂)₄NHC(O)CH₂O-4-fluorophenyl,

4-[-C≡C-(2-pyridyl)]benzyl,

4-[-C≡C—CH₂—O-phenyl]benzyl,

4-[-C≡C—CH₂OCH₃]benzyl,

4-[-C≡C-(3-hydroxyphenyl)]benzyl,

4-[-C≡C—CH, —O-4′-C(O)OC₂H₅)phenyl]benzyl,

4-[-C≡C—CH₂CH(C(O)OCH₃)₂]benzyl,

4-[-C≡C—CH₂NH-(4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl),

3-aminobenzyl,

4-[-C≡C—CH₂CH(NHC(O)CH₃)C(O)OH]-benzyl,

—CH₂C(O)NHCH(CH₃)φ,

—CH₂C(O)NHCH₂-(4-dimethylamino)-φ,

—CH₂C(O)NHCH₂-4-nitrophenyl,

—CH₂CH₂C(O)N(CH₃)CH₂-φ),

—CH₂CH₂C(O)NHCH₂CH₂—(N-methyl)-2-pyrrolyl,

—CH₂CH₂C(O)NHCH₂CH₂CH₂CH₃,

—CH₂CH₂C(O)NHCH₂CH₂-3-indolyl,

—CH₂C(O)N(CH₃)CH₂-phenyl,

—CH₂C(O)NH(CH₂)₂—(N-methyl)-2-pyrrolyl,

—CH₂C(O)NHCH₂CH₂CH₂CH₃,

—CH₂C(O)NHCH₂CH₂-3-indolyl,

—(CH₂)₂C(O)NHCH(CH₃)φ,

—(CH₂)₂C(O)NHCH₂-4-dimethylaminophenyl,

—(CH₂)₂C(O)NHCH₂-4-nitrophenyl,

—CH₂C(O)NH-4-[-NHC(O)CH₃-phenyl],

—CH₂C(O)NH-4-pyridyl,

—CH₂C(O)NH-4-[dimethylaminophenyl],

—CH₂C(O)NH-3-methoxyphenyl,

—CH₂CH₂C(O)NH-4-chlorophenyl,

—CH₂CH₂C(O)NH-2-pyridyl,

—CH₂CH₂C(O)NH-4-methoxyphenyl,

—CH₂CH₂C(O)NH-3-pyridyl,

4-[(CH₃)₂NCH₂CH₂O-]benzyl,

—(CH₂)₃NHC(NH)NH—SO₂-4-methylphenyl,

4-[(CH₃)₂NCH₂CH₂O-]benzyl,

—(CH₂)₄NHC(O)NHCH₂CH₃,

—(CH₂)₄NHC(O)NH-phenyl,

—(CH₂)₄NHC(O)NH-4-methoxyphenyl,

4-[4′-pyridyl-C(O)NH-]benzyl,

4-[3′-pyridyl-C(O)NH-]benzyl,

4-[-NHC(O)NH-3′-methylphenyl]benzyl,

4-[-NHC(O)CH₂NHC(O)NH-3′-methylphenyl]benzyl,

4-[-NHC(O)-(2,3′-dihydroindol-2-yl)]benzyl,

4-[-NHC(O)-(2′,3′-dihydro-N-Boc-indol-2-yl)]benzyl,

p-[-OCH₂CH₂-1′-(4′-pyrimidinyl)-piperazinyl]benzyl,

4-[-OCH₂CH₂-(1′-piperidinyl]benzyl,

4-[-OCH₂CH₂-(1′-pyrrolidinyl)]benzyl,

4-[-OCH₂CH₂CH₂-(1′-piperidinyl)]benzyl-,

—CH₂-3-(1,2,4-triazolyl),

4-[-OCH₂CH₂CH₂-4-(3′-chlorophenyl)-piperazin-1-yl]benzyl,

4-[-OCH₂CH₂N(φ)CH₂CH₃]benzyl,

4-[-OCH₂-3′-(N-Boc)-piperidinyl]benzyl,

4-[di-n-pentylamino]benzyl,

4-[n-pentylamino]benzyl,

4-[di-iso-propylamino-CH₂CH₂O-]benzyl,

4-[-OCH₂CH₂—(N-Morpholinyl)]benzyl,

4-[O-(3′-(N-Boc)-piperidinyl]benzyl,

4-[-OCH₂CH(NHBoc)CH₂cyclohexyl]benzyl,

p-[OCH₂CH₂—(N-piperidinyl]benzyl,

4-[-OCH₂CH₂CH₂-(4-m-chlorophenyl)-piperazin-1-yl]benzyl,

4-[-OCH₂CH₂—(N-homopiperidinyl)benzyl,

4-[-NHC(O)-3-(N-Boc)-piperidinyl]benzyl,

4-[-OCH₂CH₂N(benzyl)₂]benzyl,

—CH₂-2-thiazolyl,

3-hydroxybenzyl,

4-[-OCH₂CH₂CH₂N(CH₃)₂]benzyl,

4-[-NHC(S)NHCH₂CH₂—(N-morpholino)]benzyl,

4-[-OCH₂CH₂N(C₂H₅)₂]benzyl,

4-[-OCH₂CH₂CH₂N(C₂H₅)₂]benzyl,

4-[CH₃(CH₂)₄NH-]benzyl,

4-[N-n-butyl,N-n-pentylamino]benzyl,

4-[-NHC(O)-4′-piperidinyl]benzyl,

4-[-NHC(O)CH(NHBoc)(CH₂)₄NHCbz]benzyl,

4-[-NHC(O)-(1′,2′,3′,4′-tetrahydro-N-Boc-isoquinolin-1′-yl]benzyl,

p-[-OCH₂CH₂CH₂-1′-(4′-methyl)-piperazinyl]benzyl,

—(CH₂)₄NH-Boc,

3-[-OCH₂CH₂CH₂N(CH₃)₂]benzyl,

4-[-OCH₂CH₂CH₂N(CH₃)₂]-benzyl,

3-[-OCH₂CH₂-(1′-pyrrolidinyl)]benzyl,

4-[-OCH₂CH₂CH₂N(CH₃)benzyl]benzyl,

4-[-NHC(S)NHCH₂CH₂CH₂—(N-morpholino)]benzyl,

4-[-OCH₂CH₂—(N-morpholino)]benzyl,

4-[-NHCH₂-(4′-chlorophenyl)]benzyl,

4-[-NHC(O)NH-(4′-cyanophenyl)]benzyl,

4-[-OCH₂COOH]benzyl,

4-[-OCH₂COO-t-butyl]benzyl,

4-[-NHC(O)-5′-fluoroindol-2-yl]benzyl,

4-[-NHC(S)NH(CH₂)₂-1-piperidinyl]benzyl,

4-[-N(SO₂CH₃)(CH₂)₃—N(CH₃)₂]benzyl,

4-[—NHC(O)CH₂CH(C(O)OCH₂φ)-NHCbz]benzyl,

4-[-NHS(O)₂CF₃]benzyl,

3-[-O—(N-methylpiperidin-4′-yl]benzyl,

4-[-C(═NH)NH₂]benzyl,

4-[-NHSO₂—CH₂Cl]benzyl,

4-[-NHC(O)-(1′,2′,3′,4′-tetrahydroisoquinolin-2′-yl]benzyl,

4-[-NHC(S)NH(CH₂)₃—N-morpholino]benzyl,

4-[-NHC(O)CH(CH₂CH₂CH₂CH₂NH₂)NHBoc]benzyl,

4-[-C(O)NH₂]benzyl,

4-[-NHC(O)NH-3′-methoxyphenyl]benzyl,

4-[-OCH₂CH₂-indol-3′-yl]benzyl,

4-[-OCH₂C(O)NH-benzyl]benzyl,

4-[-OCH₂C(O)O-benzyl]benzyl,

4-[-OCH₂C(O)OH]benzyl,

4-[-OCH₂-2′-(4′,5′-dihydro)imidazolyl]benzyl,

—CH₂C(O)NHCH₂-(4-dimethylamino)phenyl,

—CH₂C(O)NHCH₂-(4-dimethylamino)phenyl,

4-[-NHC(O)-L-2′-pyrrolidinyl-N—SO₂-4′-methylphenyl]benzyl,

4-[-NHC(O)NHCH₂CH₂CH₃]benzyl,

4-aminobenzyl]benzyl,

4-[-OCH₂CH₂-1-(4-hydroxy-4-(3-methoxypyrrole-2-yl)-piperazinyl]benzyl,

4-[-O-(N-methylpiperidin-4′-yl)]benzyl,

3-methoxybenzyl,

4-[-NHC(O)-piperidin-3′-yl]benzyl,

4-[-NHC(O)-pyridin-2′-yl]benzyl,

4-[-NHCH₂-(4′-chlorophenyl)]benzyl,

4-[-NHC(O)—(N-(4′-CH3-φ-SO₂)-L-pyrrolidin-2′-yl)]benzyl,

4-[-NHC(O)NHCH₂CH₂-φ]benzyl,

4-[-OCH₂C(O)NH₂]benzyl,

4-[-OCH₂C(O)NH-t-butyl]benzyl,

4-[-OCH₂CH₂-1-(4-hydroxy-4-phenyl)-piperidinyl]benzyl,

4-[-NHSO₂—CH═CH₂]benzyl,

4-[-NHSO₂—CH₂CH₂Cl]benzyl,

—CH₂C(O)NHCH₂CH₂N(CH₃)₂,

4-[(1′-Cbz-piperidin-4′-yl)C(O)NH-]benzyl,

4-[(1′-Boc-piperidin-4′-yl)C(O)NH-]benzyl,

4-[(2′-bromophenyl)C(O)NH-]benzyl,

4-[-NHC(O)-pyridin-4′-yl]benzyl,

4-[(4′-(CH₃)₂NC(O)O-)phenyl)-C(O)NH-]benzyl,

4-[-NHC(O)-1′-methylpiperidin-4′-yl-]benzyl,

4-(dimethylamino)benzyl,

4-[-NHC(O)-(1′-N-Boc)-piperidin-2′-yl]benzyl,

3-[—NHC(O)-pyridin-4′-yl]benzyl,

4-[(tert-butyl-O(O)CCH₂—O-benzyl)-NH-]benzyl,

[BocNHCH₂C(O)NH-]butyl,

4-benzylbenzyl,

2-hydroxyethyl,

4-[(Et)₂NCH₂CH₂CH₂NHC(S)NH-]benzyl,

4-[(1′-Boc-4′-hydroxypyrrolidin-2′-yl)C(O)NH-]benzyl,

4-[φCH₂CH₂CH₂NHC(S)NH-]benzyl,

4-[(perhydroindolin-2′-yl)C(O)NH-]benzyl,

2-[4-hydroxy-4-(3-methoxythien-2-yl)piperidin-1-yl]ethyl,

4-[(1′-Boc-perhydroindolin-2′-yl)-C(O)NH-]benzyl,

4-[N-3-methylbutyl-N-trifluoromethanesulfonyl)amino]benzyl,

4-[N-vinylsulfonyl)amino]benzyl,

4-[2-(2-azabicyclo[3.2.2]octan-2-yl)ethyl-O-]benzyl,

4-[4′-hydroxypyrrolidin-2′-yl)C(O)NH-]benzyl,

4-(4NHC(S)NH)benzyl,

4-(EtNHC(S)NH)benzyl,

4-(4)CH₂NHC(S)NH)benzyl,

3-[(1′-Boc-piperidin-2′-yl)C(O)NH-]benzyl,

3-[piperidin-2′-yl-C(O)NH-]benzyl,

4-[(3′-Boc-thiazolidin-4′-yl)C(O)NH-]benzyl,

4-(pyridin-3′-yl-NHC(S)NH)benzyl,

4-(CH₃—NHC(S)NH)benzyl,

4-(H₂NCH₂CH₂CH₂C(O)NH)benzyl,

4-(BocHNCH₂CH₂CH₂C(O)NH)benzyl,

4-(pyridin-4′-yl-CH₂NH)benzyl,

4-[(N,N-di(4-N,N-dimethylamino)benzyl)amino]benzyl,

4-[(1-Cbz-piperidin-4-yl)C(O)NH-]butyl,

4-[φCH₂OCH₂(BocHN)CHC(O)NH]benzyl,

4-[(piperidin-4′-yl)C(O)NH-]benzyl,

4-[(pyrrolidin-2′-yl)C(O)NH-]benzyl,

4-(pyridin-3′-yl-C(O)NH)butyl,

4-(pyridin-4′-yl-C(O)NH)butyl,

4-(pyridin-3′-yl-C(O)NH)benzyl,

4-[CH₃NHCH₂CH₂CH₂C(O)NH-]benzyl,

4-[CH₃N(Boc)CH₂CH₂CH₂C(O)NH-]benzyl,

4-(aminomethyl)benzyl,

4-[φCH₂OCH₂(H₂N)CHC(O)NH]benzyl,

4-[(1′,4′-di(Boc)piperazin-2′-yl)-C(O)NH-]benzyl,

4-[(piperazin-2′-yl)-C(O)NH-]benzyl,

4-[(N-toluenesulfonylpyrrolidin-2′-yl)C(O)NH-]butyl,

4-[-NHC(O)-4′-piperidinyl]butyl,

4-[-NHC(O)-1′-N-Boc-piperidin-2′-yl]benzyl,

4-[-NHC(O)-piperidin-2′-yl]benzyl,

4-[(1′-N-Boc-2′,3′-dihydroindolin-2′-yl)-C(O)NH]benzyl,

4-(pyridin-3′-yl-CH₂NH)benzyl,

4-[(piperidin-1′-yl)C(O)CH₂—O-]benzyl,

4-[(CH₃)₂CH)₂NC(O)CH₂—O-]benzyl,

4-[HO(O)C(Cbz-NH)CHCH₂CH₂—C(O)NH-]benzyl,

4-[φCH₂O(O)C(Cbz-NH)CHCH₂CH₂—C(O)NH-]benzyl,

4-[-NHC(O)-2′-methoxyphenyl]benzyl,

4-[(pyrazin-2′-yl)C(O)NH-]benzyl,

4-[HO(O)C(NH₂)CHCH₂CH₂—C(O)NH-]benzyl,

4-(2′-formyl-1′,2′,3′,4′-tetrahydroisoquinolin-3′-yl-CH₂NH-)benzyl,

N-Cbz-NHCH₂—,

4-[(4′-methylpiperazin-1′-yl)C(O)O-]benzyl,

4-[CH₃(N-Boc)NCH₂C(O)NH-]benzyl,

4-[-NHC(O)-(1′,2′, 3′,4′-tetrahydro-N-Boc-isoquinolin-3′-yl]-benzyl,

4-[CH₃NHCH₂C(O)NH-]benzyl,

(CH₃)₂NC(O)CH₂—,

4-(N-methylacetamido)benzyl,

4-(1′,2′, 3′,4′-tetrahydroisoquinolin-3′-yl-CH₂NH-)benzyl,

4-[(CH₃)₂NHCH₂C(O)NH-]benzyl,

(1-toluenesulfonylimidizol-4-yl)methyl,

4-[(1′-Boc-piperidin-4′-yl)C(O)NH-]benzyl,

4-trifluoromethylbenzyl,

4-[(2′-bromophenyl)C(O)NH-]benzyl,

4-[(CH₃)₂NC(O)NH-]benzyl,

4-[CH₃OC(O)NH-]benzyl,

4-[(CH₃)₂NC(O)O-]benzyl

4-[(CH₃)₂NC(O)N(CH₃)-]benzyl,

4-[CH₃OC(O)N(CH₃)-]benzyl,

4-(N-methyltrifluoroacetamido)benzyl,

4-[(1′-methoxycarbonylpiperidin-4′-yl)C(O)NH-]benzyl,

4-[(4-phenylpiperidin-4′-yl)C(O)NH-]benzyl,

4-[(4′-phenyl-1′-Boc-piperidin-4′-yl)-C(O)NH-]benzyl,

4-[(piperidin-4′-yl)C(O)O-]benzyl,4-[(1′-methylpiperidin-4′-yl)-O-]benzyl,

4-[(1′-methylpiperidin-4′-yl)C(O)O-]benzyl,

4-[(4′-methylpiperazin-1′-yl)C(O)NH-]benzyl,

3-[(CH₃)₂NC(O)O-]benzyl,

4-[(4′-phenyl-1′-Boc-piperidin-4′-yl)-C(O)O-]benzyl,

4-(N-toluenesulfonylamino)benzyl,

4-[(CH₃)₃CC(O)NH-]benzyl,

4-[(morpholin-4′-yl)C(O)NH-]benzyl,

4-[(CH₃CH₂)₂NC(O)NH-]benzyl,

4-[-C(O)NH-(4′-piperidinyl)]benzyl,

4-[(2′-trifluoromethylphenyl)C(O)NH-]benzyl,

4-[(2′-methylphenyl)C(O)NR-]benzyl,

4-[(CH₃)₂NS(O)₂O-]benzyl,

4-[(pyrrolidin-2′-yl)C(O)NH-]benzyl,

4-[-NHC(O)-piperidin-1′-yl]benzyl,

4-[(thiomorpholin-4′-yl)C(O)NH-]benzyl,

4-[(thiomorpholin-4′-yl sulfone)-C(O)NH-]benzyl,

4-[(morpholin-4′-yl)C(O)O-]benzyl,

3-nitro-4-(CH₃OC(O)CH₂O-)benzyl,

(2-benzoxazolinon-6-yl)methyl-,

(2H-1,4-benzoxazin-3(4H)-one-7-yl)methyl-,

4-[(CH₃)₂NS(O)₂NH-]benzyl,

4-[(CH₃)₂NS(O)₂N(CH₃)-]benzyl,

4-[(thiomorpholin-4′-yl)C(O)O-]benzyl,

4-[(thiomorpholin-4′-yl sulfone)-C(O)O-]benzyl,

4-[(piperidin-1′-yl)C(O)O-]benzyl,

4-[(pyrrolidin-1′-yl)C(O)O-]benzyl,

4-[(4′-methylpiperazin-1′-yl)C(O)O-]benzyl,

4-[(2′-methylpyrrolidin-1′-yl)-,

(pyridin-4-yl)methyl-,

4-[(piperazin-4′-yl)-C(O)O-]benzyl,

4-[(1′-Boc-piperazin-4′-yl)-C(O)O-]benzyl,

4-[(4′-acetylpiperazin-1′-yl)C(O)O-]benzyl,

p-[(4′-methanesulfonylpiperazin-1′-yl)-benzyl,

3-nitro-4-[(morpholin-4′-yl)-C(O)O-]benzyl,

4-{[(CH₃)₂NC(S)]₂N-}benzyl,

N-Boc-2-aminoethyl-,

4-[(1,1-dioxothiomorpholin-4-yl)-C(O)O-]benzyl,

4-[(CH₃)₂NS(O)₂-]benzyl,

4-(imidazolid-2′-one-1′-yl)benzyl,

4-[(piperidin-1′-yl)C(O)O-]benzyl,

1-N-benzyl-imidazol-4-yl-CH₂—,

3,4-dioxyethylenebenzyl (i.e., 3,4-ethylenedioxybenzyl),

3,4-dioxymethylenebenzyl (i.e., 3,4-methylenedioxybenzyl),

4-[-N(SO₂)(CH₃)CH₂CH₂CH₂N(CH₃)₂]benzyl,

4-(3′-formylimidazolid-2′-one-1′-yl)benzyl,

4-[NHC(O)CH(CH₂CH₂C₁₋₁₂CH₂NH₂)NHBoc]benzyl,

[2′-[4″-hydroxy-4″-(3′″-methoxythien-2′″-yl)piperidin-2′″-yl]ethoxy]benzyl,and

p-[(CH₃)₂NCH₂CH₂N(CH₃)C(O)O-]benzyl.

Preferably, R⁵ in the above compounds is selected from the groupconsisting of alkyl, substituted alkyl, aryl, substituted aryl,heterocyclic, substituted heterocylic, heteroaryl and substitutedheteroaryl. Even more preferably R⁵ is selected from the groupconsisting of 4-methylphenyl, methyl, benzyl, n-butyl, n-hexyl,4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl,2,4,6-trimethylphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl,3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl,3,4-dimethoxyphenyl, 4-(CH₃C(O)NH—)phenyl, 4-trifluoromethoxyphenyl,4-cyanophenyl, isopropyl, 3,5-di-(trifluoromethyl)phenyl,4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl,1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl,1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl,4-methylamidinophenyl, 4-[CH₃SC(═NH)]phenyl, 5-chloro-2-thienyl,2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl,5-methyl-1,3,4-thiadiazol-2-yl, 4-[H₂NC(S)]phenyl, 4-aminophenyl,4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl,pyridin-3-yl, pyrimidin-2-yl, 4-(3′-dimethylamino-n-propoxy)-phenyl, and1-methylpyrazol-4-yl.

Preferably, R¹³ in the above compounds is selected from hydrogen or C₁₋₆alkyl; more preferably, hydrogen or C₁₋₃ alkyl; and still morepreferably, hydrogen or methyl.

In a preferred embodiment, R¹⁴ in the above compounds is preferablyhydrogen and R¹⁵ is preferably C₁₋₁₀ alkyl or Cy-C₁₋₁₀ alkyl, whereinalkyl is optionally substituted with one to four substituents selectedfrom phenyl and R^(x), and Cy is optionally substituted with one to foursubstituents independently selected from R^(y), or R₁₄ and R¹⁵ and thecarbon to which they are attached together from a 3-7 membered mono- orbicyclic carbon only ring. For the purpose of R¹⁵, Cy is preferablyaryl, more preferably phenyl. In a preferred embodiment, R¹⁵ isphenyl-C₁₋₃ alkyl, wherein phenyl is optionally substituted with one ortwo groups selected from R. Additional preferred embodiments for R¹⁴ andR¹⁵ are disclosed in International Patent Application Publication No. WO98/53814, which application is incorporated herein by reference in itsentirety.

In a preferred embodiment of the above compounds, R¹⁶ is substitutedamino; R¹⁷ and/or R²⁰ are hydrogen; and R¹⁸ and/or R²¹ are alkyl,substituted alkyl, aryl or substituted aryl.

In a preferred embodiment, R²³ in the above compounds is hydrogen.Preferably, R²⁴ in the above compounds is Ar¹—Ar²—C₁₋₁₀ alkyl whereinAr¹ and Ar² are optionally substituted with from 1 to 4 groupsindependently selected from R^(b) and R²⁵ is hydrogen. More preferably,R²⁴ is Ar¹—Ar²—C₁₋₃ alkyl wherein Ar¹ and Ar² are optionally substitutedwith from 1 to 4 groups independently selected from R^(b); still morepreferably, R²⁴ is —CH₂—Ar²—Ar¹ and R²⁵ is hydrogen. Additionalpreferred embodiments are disclosed in International Patent ApplicationPublication No. WO 98/53817, which application is incorporated herein byreference in its entirety.

Preferably, R³ and R^(3′), or R¹⁴ and R¹⁵, or R²⁴ and R²⁵ are derivedfrom L-amino acids or other similarly configured starting materials.Alternatively, racemic mixtures can be used.

Preferably, x in the above compounds is an integer from 1 to 4.

This invention also provides methods for binding VLA-4 in a biologicalsample which method comprises contacting the biological sample with acompound of this invention under conditions wherein said compound bindsto VLA-4.

The pharmaceutical compositions may be used to treat disease conditionsmediated by VLA-4 or leucocyte adhesion. Such disease conditionsinclude, by way of example, asthma, Alzheimer's disease,atherosclerosis, AIDS dementia, diabetes (including acute juvenile onsetdiabetes), inflammatory bowel disease (including ulcerative colitis andCrohn's disease), multiple sclerosis, rheumatoid arthritis, tissuetransplantation, tumor metastasis, meningitis, encephalitis, stroke, andother cerebral traumas, nephritis, retinitis, atopic dermatitis,psoriasis, myocardial ischemia and acute leukocyte-mediated lung injurysuch as that which occurs in adult respiratory distress syndrome.

Other disease conditions include, but are not limited to, inflammatoryconditions such as erythema nodosum, allergic conjunctivitis, opticneuritis, uveitis, allergic rhinitis, ankylosing spondylitis, psoriaticarthritis, vasculitis, Reiter's syndrome, systemic lupus erythematosus,progressive systemic sclerosis; polymyositis, dermatomyositis, Wegner'sgranulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporalarteritis, pericarditis, myocarditis, congestive heart failure,polyarteritis nodosa, hypersensitivity syndromes, allergy,hypereosinophilic syndromes, Churg-Strauss syndrome, chronic obstructivepulmonary disease, hypersensitivity pneumonitis, chronic activehepatitis, interstitial cystitis, autoimmune endocrine failure, primarybiliary cirrhosis, autoimmune aplastic anemia, chronic persistenthepatitis and thyroiditis.

Preferred compounds of this invention include those set forth in theTables below:

TABLE I

R⁵ R⁶ R⁷ R⁸ R⁹ X 4-CH₃-Ph- H— H— H— 4-(CH₃)₂NC(O)O— —OC(CH₃)₃ 4-CH₃-Ph-H— H— H— 4-(CH₃)₂NC(O)O— —OH 4-CH₃-Ph- CH₃— H— H— 4-(CH₃)₂NC(O)O——OC(CH₃)₃ 4-CH₃-Ph- CH₃— H— H— 4-(CH₃)₂NC(O)O— —OH 4-CH₃-Ph- 4-CH₃-Ph-H— H— 4-(CH₃)₂NC(O)O— —OH 1-CH₃- CH₃— H— H— 4-(CH₃)₂NC(O)O— —OHpyrazol-4-yl- 4-CH₃-Ph- CH₃— H— H— 4-(CH₃)₂NC(O)O— —OCH(CH₃)₂ 3-pyridyl-CH₃— H— H— 4-(CH₃)₂NC(O)O— —OC(CH₃)₃ 1-(n-C₄H₉)- CH₃— H— H—4-(CH₃)₂NC(O)O— —OC(CH₃)₃ pyrazol-4-yl- 4-CH₃-Ph- CH₃— H— H— H— —OH1-(n-C₄H₉)- CH₃— H— H— 4-(CH₃)₂NC(O)O— —OH pyrazol-4-yl- 3-pyridyl- CH₃—H— H— 4-(CH₃)₂NC(O)O— —OH 4-CH₃-Ph- CH₃— (CH₃)₂N— H— H— —OH 1-CH₃- CH₃—H— H— 4-(CH₃)₂NC(O)O— —OCH(CH₃)₂ pyrazol-4-yl- 3-pyridyl- CH₃— H— H—4-(1-CH₃-piperazin- —OCH(CH₃)₂ 4-yl)C(O)O— 3-pyridyl- CH₃— H— H—4-(1-CH₃-piperazin- —OC(CH₃)₃ 4-yl)C(O)O— 3-pyridyl- CH₃— H— H—4-(1-CH₃-piperazin- —OH 4-yl)C(O)O— Ph = phenyl

TABLE II

R^(16′) R^(20′) R^(18′) R¹⁹ X Cl— H— NO₂— 4-(CH₃)₂NC(O)O— —OH H— H—PhCH₂O— H— —OH H— H— PhCH₂O— 4-(CH₃)₂NC(O)O— —OH H— H— Ph-4-(CH₃)₂NC(O)O— —OH H H 3-NO₂-Ph- 4-(CH₃)₂NC(O)O— —OH H— H— 3-pyridyl-4-(CH₃)₂NC(O)O— —OH H— H— 2-PhCH₂CH₂— 4-(CH₃)₂NC(O)O— —OH H— H—2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH H— H— (CH₃)₂NC(O)— 4-(CH₃)₂NC(O)O— —OH(CH₂)₂— H— Ph- H— 4-(CH₃)₂NC(O)O— —OH H— 2-CF₃-Ph- H— 4-(CH₃)₂NC(O)O——OH H— 2-HOCH₂Ph- H— 4-(CH₃)₂NC(O)O— —OH H— H— CF₃CH₂— 4-(CH₃)₂NC(O)O——OH H— H— PhCH₂— 4-(CH₃)₂NC(O)O— —OH H— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O——OCH(CH₃)₂ H— H— 2-PhCH₂CH₂— 4-(CH₃)₂NC(O)O— —OCH(CH₃)₂ H— H—2-PhCH₂CH₂— H— —OCH(CH₃)₂ cyclohexyl- H— H— 4-(CH₃)₂NC(O)O— —OH (CH₃)N—H— H— CH₃CH₂CH₂— 4-(CH₃)₂NC(O)O— —OH H— H— 2-CH₃O-Ph- 4-(CH₃)₂NC(O)O——OH H— H— 2-F-Ph- 4-(CH₃)₂NC(O)O— —OH (CH₃)₂CH— H— 2-CH₃-Ph-4-(CH₃)₂NC(O)O— —OH (CH₃)N— (CH₃)₂CH—NH— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O——OH (CH₃)₂CHCH₂— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH (CH₃)N— CH₃CH₂CH₂— H—2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH (CH₃)N— (CH₃)₂N— H— 2-CH₃-Ph-4-(CH₃)₂NC(O)O— —OH cyclohexyl- H— 3-pyridyl- 4-(CH₃)₂NC(O)O— —OH(CH₃)N— H— H— 2-PhCF₂CH₂— 4-(CH₃)₂NC(O)O— —OH H— Cl- 2-PhCF₂CH₂—4-(CH₃)₂NC(O)O— —OH (HOCH₂CH₂)₂N— H— H— 4-(CH₃)₂NC(O)O— —OH(HOCH₂CH₂)₂N— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH Ph(CH₃)N— H— 2-CH₃-Ph-4-(CH₃)₂NC(O)O— —OH (CH₃)₂CHO— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH(CH₃)₂CHCH₂— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH CH₂(CH₃)N— CH₃NH— H—2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH 2-CH₃-Ph- H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OHHOCH₂CH₂— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH (CH₃)N— cyclohexyl-NH— H—2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH 1-CH₃-piperidin- H— 2-CH₃-Ph-4-(CH₃)₂NC(O)O— —OH 4-yl-(CH₃)N— (CH₃)₂CH— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O——OH (CH₃CH₂—)N— H— H— 2,4,6-tri-CH₃- 4-(CH₃)₂NC(O)O— —OH Ph- H— H—(CH₃)₂CH— 4-(CH₃)₂NC(O)O— —OH CH₃(CH₂)₃— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O——OH (CH₃)N— CH₃CH₂CH₂— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH (CH₃CH₂—)N—(CH₃CH₂)₂N— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH CH₃CH₂— H— 2-CH₃-Ph-4-(CH₃)₂NC(O)O— —OH (CH₃)N— H— H— cyclohexyl- 4-(CH₃)₂NC(O)O— —OH(furan-2-yl)CH₂— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH (CH₃)N—4-Cl-Ph-(CH₃)N— H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH H— H— thien-3-yl-4-(CH₃)₂NC(O)O— —OH H— H— thien-2-yl- 4-(CH₃)₂NC(O)O— —OH HOCH₂CH₂— H—2-F-Ph- 4-(CH₃)₂NC(O)O— —OH (CH₃)N— H— H— piperidin-1-yl-4-(CH₃)₂NC(O)O— —OH H— H— (CH₃CH₂CH₂)₂— 4-(CH₃)₂NC(O)O— —OH CH—cyclobutyl- H— 2-CH₃-Ph- 4-(CH₃)₂NC(O)O— —OH (CH₃)N— H— H— 2-HOCH₂-Ph-4-(CH₃)₂NC(O)O— —OH H— H— 2,6-di-F-Ph- 4-(CH₃)₂NC(O)O— —OH H— H—2,4-di-CH₃O- 4-(CH₃)₂NC(O)O— —OH pyrimidin-5-yl cyclohexyl- H— 2-CH₃-Ph-4-(CH₃)₂NC(O)O— —OH (CH₃)N— H— H— 2-CF₃-Ph- 4-(CH₃)₂NC(O)O— —OHcyclohexyl- H— 2-CH₃O-Ph- 2,6-di-CH₃O-Ph- —OH (CH₃)N— (CH₃)₂CH— H—2-F-Ph- 2,6-di-CH₃O-Ph- —OH (CH₃)N— (CH₃)₂CH— H— 2-F-Ph- 2-CH₃O-Ph- —OH(CH₃)N— cyclohexyl- H— 2,6-di-F-Ph- 2,6-di-F-Ph- —OH (CH₃)N— cyclohexyl-H— 2-HOCH₂-Ph- 2,6-di-CH₃O-Ph- —OH (CH₃)N— (HOCH₂CH₂)₂N— H—2,4,6-tri-CH₃- 2,6-di-CH₃O-Ph- —OH Ph- cyclohexyl- H— 2-CF₃-Ph- 2-NC-Ph-—OH (CH₃)N— cyclohexyl- H— thien-3-yl- 2,6-di-CH₃O-Ph- —OH (CH₃)N—cyclohexyl- H— thien-2-yl- 4-CF₃-Ph- —OH (CH₃)N— cyclohexyl- H—3-pyridyl- 2,6-di-CH₃O-Ph- —OH (CH₃)N— cyclohexyl- H— 3-NO₂-Ph-2,6-di-CH₃O-Ph- —OH (CH₃)N— cyclohexyl- H— 2,6-di-Cl-Ph- 2,6-di-CH₃O-Ph-—OH (CH₃)N— cyclohexyl- H— 4-pyridyl- 3-HOCH₂-Ph- —OH (CH₃)N— (CH₃)₂CH—H— 2,6-di-CH₃O- 2,6-di-CH₃O-Ph- —OH (CH₃CH₂—)N— Ph- cyclohexyl- H—2,3-di-Cl-Ph- 2,6-di-CH₃O-Ph- —OH (CH₃)N— CH₃CH₂— H— 2,4,6-tri-CH₃-2-NC-Ph- —OH (CH₃)N— Ph- (CH₃)₂CH— H— 2,4,6-tri-CH₃- 3-pyridyl- —OH(CH₃)N— Ph- (HOCH₂CH₂)₂N— H— 2,4,6-tri-CH₃- 2-NC-Ph- —OH Ph-1-CH₃-piperidin- H— 2-NC-Ph- 2,6-di-F-Ph- —OH 4-yl-(CH₃)N— (CH₃)₂CH— H—2,4,6-tri-CH₃- 2-CH₃-Ph- —OH (CH₃CH₂—)N— 4-Cl-Ph-(CH₃)N— H—2,4,6-tri-CH₃- 2,6-di-CH₃O-Ph- —OH Ph- H— H— PhCH₂CH₂— 4-(CH₃)₂NC(O)O——OH (CH₃)N— H— H— CH₃(CH₂)₅— 4-(CH₃)₂NC(O)O— —OH (CH₃)N— H— H— (CH₃)₂CH—4-(CH₃)₂NC(O)O— —OH (CH₃)N— H— H— (CH₃)₃C— 4-(CH₃)₂NC(O)O— —OH (CH₃)N—H— H— (CH₃)₂CH— 4-(CH₃)₂NC(O)O— —OH (CH₃CH₂—)N— H— H— 4-pyridyl-4-(CH₃)₂NC(O)O— —OH CH₂CH₂— (CH₃)N— H— H— PhCH₂CH₂— 2,6-di-CH₃O-Ph- —OH(CH₃)N— H— H— CH₃(CH₂)₅— 2,6-di-CH₃O-Ph- —OH (CH₃)N— H— H— (CH₃)₂CH—2,6-di-CH₃O-Ph- —OH (CH₃)N— H— H— (CH₃)₃C— 2,6-di-CH₃O-Ph- —OH (CH₃)N—H— H— (CH₃)₂CH— 2,6-di-CH₃O-Ph- —OH (CH₃CH₂—)N— H— H— 4-pyridyl-2,6-di-CH₃O-Ph- —OH CH₃CH₂— (CH₃)N— cyclohexyl- H— CH₃CH₂—4-(CH₃)₂NC(O)O— —OH (CH₃)N— H— H— CF₃CH₂— 2,6-di-CH₃O-Ph- —OHcyclohexyl- H— 2-CH₃-Ph- 2,6-di-CH₃O-Ph- —OH (CH₃)N— H— H— 2-F-Ph-2,6-di-CH₃O-Ph- —OH CH₃CH₂CH₂— H— 2-CH₃-Ph- 2,6-di-CH₃O-Ph- —OH (CH₃)N—Ph = phenyl

TABLE III

R⁵ R⁶ R^(7′) R^(8′) R^(9′) X 4-CH₃-Ph- CH₃— H— H— 4-(CH₃)₂NC(O)O— —OH4-CH₃-Ph- CH₃— H— H— 4-(CH₃)₂NC(O)O— —OCH(CH₃)₂ Ph = phenyl

TABLE IV

R⁵ R⁶ b R^(9′) X CH₃(CH₂)₅— CH₃(CH₂)₅— 2 4-HO— —OH CH₃(CH₂)₅— CH₃(CH₂)₅—2 4-(CH₃)₂NC(O)O— —OH CH₃— CH₃— 1 4-(CH₃)₂NC(O)O— —OC(CH₃)₃ 3-CH₃-PhNH—H— 2 4-(CH₃)₂NC(O)O— —OH C(O)NH(CH₂)₂— CH₃(CH₂)₅— CH₃(CH₂)₅— 2 4-(1-CH₃-—OH piperazin-4-yl)C(O)O— Ph = phenyl

Accordingly, this invention is also directed to each of the followingcompounds:

-   N-(2-chloro-5-nitropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-[5-(N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    tert-butyl ester,-   N-[5-(N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-[5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    tert-butyl ester,-   N-[5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-[5-(N,N-di-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-[5-[N-(1-N′-methylpyrazol-4-ylsulfonyl)-N-methylamino]pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-[5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    isopropyl ester,-   N-[5-(N-methyl-N-3-pyridylsulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    tert-butyl ester,-   N-(5-(N-methyl-N-(1-butylpyrazol-4-yl)sulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2,4-dimethoxypyrimidin-5-yl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2,6-difluorophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(N,N-    dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-cyclohexylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-(1-methylpiperidin-4-yl)amino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-ethyl-N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2,4-6-trimethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-isopropylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-butylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-ethyl-N-propylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N,N-diethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-ethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-benzyloxypyrimidin-4-yl)-L-phenylalanine,-   N-(5-benzyloxypyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-phenylalanine,-   N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-phenylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(3-(N-methyl-N-4-toluenesulfonylamino)pyrazin-2-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine    isopropyl ester,-   N-(5-benzylpyrimidine-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine    tert-butyl ester,-   N-(5-(2-trifluoromethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-N,N-dimethylcarbamylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(N-methyl-N-3-(1-methylpyrazole)sulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    isopropyl ester,-   N-(6-phenylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(6-(2-trifluoromethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(6-(2-hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-cyclohexylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-2-furanmethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-4-chlorophenylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(3-thienyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-thienyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-2-hydroxyethylamino)-5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(piperidin-1-yl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(1-propylbutyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-cyclobutylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N,N-bis-(2-hydroxyethyl)amino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,

N-(2-(N-methyl-N-phenylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,

-   N-(2-(isopropoxy)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-3-methylbutylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(2-tolyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-2-hydroxyethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-2-methylpropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-propylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N,N-dimethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(3-pyridyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-phenyl-2,2-difluoroethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-phenyl-2,2-difluoroethyl)-6-chloropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-propylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-methoxyphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-Methyl-N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    isopropyl ester,-   N-(3-(N-methyl-N-4-toluenesulfonylamino)pyrazin-2-yl)-L-phenylalanine    isopropyl ester,-   N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-phenylalanine isopropyl ester,-   N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-ethylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    isopropyl ester,-   N-(5-(3-nitrophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(3-pyridyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-N,N-dimethylamino-5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-phenylalanine,-   N-(5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2-methoxyphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-isopropylamino)-5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-isopropylamino)-5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(2-methoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2,6-difluorophenyl)pyrimidin-4-yl)-L-4-(2,6-difluorophenyl)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2-hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2-trifluoromethylphenyl)pyrimidin-4-yl)-L-4-(2-cyanophenyl)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(3-thienyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2-thienyl)pyrimidin-4-yl)-L-4-(4-trifluoromethylphenyl)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(3-pyridyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(3-nitrophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2,6-dichlorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-(4-pyridyl)pyrimidin-4-yl)-L-4-(3-hydroxymethylphenyl)phenylalanine,

N42-(N-ethyl-N-isopropylamino)-5-(2,6-dimethoxyphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,

-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2,3-dichlorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-ethylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2-cyanophenyl)phenylalanine,-   N-(2-(N-methyl-N-isopropylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(3-pyridyl)phenylalanine,-   N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2-cyanophenyl)phenylalanine,-   N-(2-(N-methyl-N-(1-methylpiperidin-4-yl)amino)-5-(2-cyanophenyl)pyrimidin-4-yl)-L-4-(2,6-difluorophenyl)phenylalanine,-   N-(2-(N-ethyl-N-isopropylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(o-tolyl)phenylalanine,-   N-(2-(N-methyl-N-4-chlorophenylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(5-(N-methyl-N-2-(phenyl)ethylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(N-methyl-N-hexylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(N-methyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(N-methyl-N-tert-butylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(N-ethyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(N-methyl-N-2-(4-pyridyl)ethyl-pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(5-(N-methyl-N-2-(phenylethylamino)pyrimidin-4-yl)-L-4-(4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(5-(N-methyl-N-hexylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(5-(N-methyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(5-(N-methyl-N-tert-butylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(5-(N-ethyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(5-(N-methyl-N-2-(4-pyridyl)ethyl-pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-cyclohexylamino)-5-ethylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosine,-   N-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine,-   N-(4-(N,N-dimethylamino)-1-oxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    tert-butyl ester,-   N-[4-(2-(3-methylphenylaminocarbonylamino)eth-1-ylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine-   N-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine,-   N-(5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-cyclohexyl-N-methyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(2-(N-methyl-N-propyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine,-   N-(3-chloropyrazin-2-yl)-L-4-[1-(tert-butoxycarbonyl)piperidin-4-ylcarbonylamino]phenylalanine    ethyl ester,

and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

As above, this invention relates to compounds which inhibit leukocyteadhesion and, in particular, leukocyte adhesion mediated by VLA-4.However, prior to describing this invention in further detail, thefollowing terms will first be defined.

DEFINITIONS

As used herein, “alkyl” refers to alkyl groups preferably having from 1to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term isexemplified by groups such as methyl, t-butyl, n-heptyl, octyl and thelike.

“Substituted alkyl” refers to an alkyl group, preferably of from 1 to 10carbon atoms, having from 1 to 5 substituents selected from the groupconsisting of alkoxy, substituted alkoxy, acyl, acylamino,thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino,aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl,substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl,carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl,carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substitutedaryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl, —NRS(O),—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andsubstituted alkyl groups having amino groups blocked by conventionalblocking groups such as Boc, Cbz, formyl, and the like oralkyl/substituted alkyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkoxy” refers to the group “alkyl-O—” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” refers to the group “substituted alkyl-O—”.

“Alkenoxy” refers to the group “alkenyl-O—”.

“Substituted alkenoxy” refers to the group “substituted alkenyl-O—”.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)— cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—,substituted heteroaryl-C(O), heterocyclic-C(O)—, and substitutedheterocyclic-C(O)— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acylamino” refers to the group —C(O)NRR where each R is independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic and whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Thiocarbonylamino” refers to the group —C(S)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form, together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, heteroaryl-C(O)O—, substitutedheteroaryl-C(O)O—, heterocyclic-C(O)O—, and substitutedheterocyclic-C(O)O— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxysulfonyl” refers to the groups alkyl-SO₂O—, substituted alkyl-SO₂O—,alkenyl-SO₂O—, substituted alkenyl-SO₂O—, alkynyl-SO₂O—, substitutedalkynyl-SO₂O—, aryl-SO₂O—, substituted aryl-SO₂O—, cycloalkyl-SO₂O—,substituted cycloalkyl-SO₂O—, heteroaryl-SO₂O—, substitutedheteroaryl-SO₂O—, heterocyclic-SO₂O—, and substituted heterocyclic-SO₂O—wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic- are as defined herein.

“Alkenyl” refers to alkenyl group preferably having from 2 to 10 carbonatoms and more preferably 2 to 6 carbon atoms and having at least 1 andpreferably from 1-2 sites of alkenyl unsaturation.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andsubstituted alkenyl groups having amino groups blocked by conventionalblocking groups such as Boc, Cbz, formyl, and the like oralkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Alkynyl” refers to alkynyl group preferably having from 2 to 10 carbonatoms and more preferably 3 to 6 carbon atohis and having at least 1 andpreferably from 1-2 sites of alkynyl unsaturation.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl; carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O), —NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkylamino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andsubstituted alkynyl groups having amino groups blocked by conventionalblocking groups such as Boc, Cbz, formyl, and the like oralkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Amidino” refers to the group H₂NC(═NH)— and the term “alkylamidino”refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC(═NH)—).

“Thioamidino” refers to the group RSC(═NH)— where R is hydrogen oralkyl.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NRR, where each R group isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl,—SO₂-substituted alkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl,—SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —SO₂-heterocyclic, —SO₂-substituted heterocyclic, providedthat both R groups are not hydrogen; or the R groups can be joinedtogether with the nitrogen atom to form a heterocyclic or substitutedheterocyclic ring.

“Aminoacyl” refers to the groups —NRC(O)alkyl, —NRC(O)substituted alkyl,—NRC(O)cycloalkyl, —NRC(O)substituted cycloalkyl, —NRC(O)alkenyl,—NRC(O)substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl,—NRC(O)aryl, —NRC(O)substituted aryl, —NRC(O)heteroaryl,—NRC(O)substituted heteroaryl, —NRC(O)heterocyclic, and—NRC(O)substituted heterocyclic where R is hydrogen or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminosulfonyl” refers to the groups —NRSO₂alkyl, —NRSO₂substitutedalkyl, —NRSO₂cycloalkyl, —NRSO₂substituted cycloalkyl, —NRSO₂alkenyl,—NRSO₂substituted alkenyl, —NRSO₂alkynyl, —NRSO₂substituted alkynyl,—NRSO₂aryl, —NRSO₂substituted aryl, —NRSO₂heteroaryl, —NRSO₂substitutedheteroaryl, —NRSO₂heterocyclic, and —NRSO₂substituted heterocyclic whereR is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminocarbonyloxy” refers to the groups —NRC(O)O-alkyl,—NRC(O)O-substituted alkyl, —NRC(O)O-alkenyl, —NRC(O)O-substitutedalkenyl, —NRC(O)O-alkynyl, —NRC(O)O-substituted alkynyl,—NRC(O)O-cycloalkyl, —NRC(O)O-substituted cycloalkyl, —NRC(O)O-aryl,—NRC(O)O-substituted aryl, —NRC(O)O-heteroaryl, —NRC(O)O-substitutedheteroaryl, —NRC(O)O-heterocyclic, and —NRC(O)O-substituted heterocyclicwhere R is hydrogen or alkyl and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonyloxy” refers to the groups —NRSO₂O-alkyl,—NRSO₂O-substituted alkyl, —NRSO₂O-alkenyl, —NRSO₂O-substituted alkenyl,—NRSO₂O-alkynyl, —NRSO₂O-substituted alkynyl, —NRSO₂O-cycloalkyl,—NRSO₂O-substituted cycloalkyl, —NRSO₂O-aryl, —NRSO₂O-substituted aryl,—NRSO₂O-heteroaryl, —NRSO₂O-substituted heteroaryl,—NRSO₂O-heterocyclic, and —NRSO₂O-substituted heterocyclic where R ishydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxycarbonylamino” refers to the groups —OC(O)NH₂, —OC(O)NRR,—OC(O)NR-alkyl, —OC(O)NR-substituted alkyl, —OC(O)NR-alkenyl,—OC(O)NR-substituted alkenyl, —OC(O)NR-alkynyl, —OC(O)NR-substitutedalkynyl, —OC(O)NR-cycloalkyl, —OC(O)NR-substituted cycloalkyl,—OC(O)NR-aryl, —OC(O)NR-substituted aryl, —OC(O)NR-heteroaryl,—OC(O)NR-substituted heteroaryl, —OC(O)NR-heterocyclic, and—OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form, together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl; cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxythiocarbonylamino” refers to the groups —OC(S)NH₂, —OC(S)NRR,—OC(S)NR-alkyl, —OC(S)NR-substituted alkyl, —OC(S)NR-alkenyl,—OC(S)NR-substituted alkenyl, —OC(S)NR-alkynyl, —OC(S)NR-substitutedalkynyl, —OC(S)NR-cycloalkyl, —OC(S)NR-substituted cycloalkyl,—OC(S)NR-aryl, —OC(S)NR-substituted aryl, —OC(S)NR-heteroaryl,—OC(S)NR-substituted heteroaryl, —OC(S)NR-heterocyclic, and—OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxysulfonylamino” refers to the groups —OSO₂NH₂, —OSO₂NRR,—OSO₂NR-alkyl, —OSO₂NR-substituted alkyl, —OSO₂NR-alkenyl,—OSO₂NR-substituted alkenyl, —OSO₂NR-alkynyl, —OSO₂NR-substitutedalkynyl, —OSO₂NR-cycloalkyl, —OSO₂NR-substituted cycloalkyl,—OSO₂NR-aryl, —OSO₂NR-substituted aryl, —OSO₂NR-heteroaryl,—OSO₂NR-substituted heteroaryl, —OSO₂NR-heterocyclic, and—OSO₂NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form, together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminocarbonylamino” refers to the groups —NRC(O)NRR, —NRC(O)NR-alkyl,—NRC(O)NR-substituted alkyl, —NRC(O)NR-alkenyl, —NRC(O)NR-substitutedalkenyl, —NRC(O)NR-alkynyl, —NRC(O)NR-substituted alkynyl,—NRC(O)NR-aryl, —NRC(O)NR-substituted aryl, —NRC(O)NR-cycloalkyl,—NRC(O)NR-substituted cycloalkyl, —NRC(O)NR-heteroaryl, and—NRC(O)NR-substituted heteroaryl, —NRC(O)NR-heterocyclic, and—NRC(O)NR-substituted heterocyclic where each R is independentlyhydrogen, alkyl or where each R is joined to form together with thenitrogen atom a heterocyclic or substituted heterocyclic ring as well aswhere one of the amino groups is blocked by conventional blocking groupssuch as Boc, Cbz, formyl, and the like and wherein alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

“Aminothiocarbonylamino” refers to the groups —NRC(S)NRR,—NRC(S)NR-alkyl, —NRC(S)NR-substituted alkyl, —NRC(S)NR-alkenyl,—NRC(S)NR-substituted alkenyl, —NRC(S)NR-alkynyl, —NRC(S)NR-substitutedalkynyl, —NRC(S)NR-aryl, —NRC(S)NR-substituted aryl,—NRC(S)NR-cycloalkyl, —NRC(S)NR-substituted cycloalkyl,—NRC(S)NR-heteroaryl, and —NRC(S)NR-substituted heteroaryl,—NRC(S)NR-heterocyclic, and —NRC(S)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminosulfonylamino” refers to the groups —NRSO₂NRR, —NRSO₂NR-alkyl,—NRSO₂NR-substituted alkyl, —NRSO₂NR-alkenyl, —NRSO₂NR-substitutedalkenyl, —NRSO₂NR-alkynyl, —NRSO₂NR-substituted alkynyl, —NRSO₄NR-aryl,—NRSO₂NR-substituted aryl, —NRSO₂NR-cycloalkyl, —NRSO₂NR-substitutedcycloalkyl, —NRSO₂NR-heteroaryl, and —NRSO₂NR-substituted heteroaryl,—NRSO₂NR-heterocyclic, and —NRSO₂NR-substituted heterocyclic, where eachR is independently hydrogen, alkyl or where each R is joined to formtogether with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic group offrom 6 to 14 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed rings (e.g., naphthyl or anthryl) which condensedrings may or may not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7yl, and the like). Preferred aryls includephenyl and naphthyl.

Substituted aryl refers to aryl groups which are substituted with from 1to 3 substituents selected from the group consisting of hydroxy, acyl,acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl,aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl,substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, ═NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkylamino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andamino groups on the substituted aryl blocked by conventional blockinggroups such as Boc, Cbz, formyl, and the like or substituted with—SO₂NRR where R is hydrogen or alkyl.

“Aryloxy” refers to the group aryl-O— which includes, by way of example,phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to substituted aryl-O— groups.

“Aryloxyaryl” refers to the group -aryl-O-aryl.

“Substituted aryloxyaryl” refers to aryloxyaryl groups substituted withfrom 1 to 3 substituents on either or both aryl rings selected from thegroup consisting of hydroxy, acyl, acylamino, thiocarbonylamino,acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic; cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl; —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andamino groups on the substituted aryl blocked by conventional blockinggroups such as Boc, Cbz, formyl, and the like or substituted with—SO₂NRR where R is hydrogen or alkyl.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 8 carbon atomshaving a single cyclic ring including, by way of example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. Excludedfrom this definition are multi-ring alkyl groups such as adamantanyl,etc.

“Cycloalkenyl” refers to cyclic alkenyl groups of from 3 to 8 carbonatoms having single or multiple unsaturation but which are not aromatic.

“Substituted cycloalkyl” and “substituted cycloalkenyl” refer to acycloalkyl and cycloalkenyl groups, preferably of from 3 to 8 carbonatoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O),—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substitutedheteroaryl, —NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substitutedheterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino,mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- anddi-substituted arylamino, mono- and di-heteroarylamino, mono- anddi-substituted heteroarylamino, mono- and di-heterocyclic amino, mono-and di-substituted heterocyclic amino, unsymmetric di-substituted amineshaving different substituents selected from alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclicand substituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkynyl/substituted alkynyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

“Cycloalkoxy” refers to —O-cycloalkyl groups.

“Substituted cycloalkoxy” refers to —O-substituted cycloalkyl groups.

“Cycloalkenoxy” refers to —O-cycloalkenyl groups.

“Substituted cycloalkenoxy” refers to —O-substituted cycloalkenylgroups.

“Guanidino” refers to the groups —NRC(═NR)NRR, —NRC(═NR)NR-alkyl,—NRC(═NR)NR-substituted alkyl, —NRC(═NR)NR-alkenyl,—NRC(═NR)NR-substituted alkenyl, —NRC(═NR)NR-alkynyl,—NRC(═NR)NR-substituted alkynyl, —NRC(═NR)NR-aryl,—NRC(═NR)NR-substituted aryl, —NRC(═NR)NR-cycloalkyl,—NRC(═NR)NR-heteroaryl, —NRC(═NR)NR-substituted heteroaryl,—NRC(═NR)NR-heterocyclic, and —NRC(═NR)NR-substituted heterocyclic whereeach R is independently hydrogen and alkyl as well as where one of theamino groups is blocked by conventional blocking groups such as Boc,Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Guanidinosulfone” refers to the groups —NRC(═NR)NRSO₂-alkyl,—NRC(═NR)NRSO₂-substituted alkyl, —NRC(═NR)NRSO₂-alkenyl,—NRC(═NR)NRSO₂-substituted alkenyl, —NRC(═NR)NRSO₂-alkynyl,—NRC(═NR)NRSO₂-substituted alkynyl, —NRC(═NR)NRSO₂-aryl,—NRC(═NR)NRSO₂-substituted aryl, —NRC(═NR)NRSO₂-cycloalkyl,—NRC(═NR)NRSO₂-substituted cycloalkyl, —NRC(═NR)NRSO₂-heteroaryl, and—NRC(═NR)NRSO₂-substituted heteroaryl, —NRC(═NR)NRSO₂ heterocyclic, and—NRC(═NR)NRSO₂-substituted heterocyclic where each R is independentlyhydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either chloro or bromo.

“Heteroaryl” refers to an aromatic carbocyclic group of from 2 to 10carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen andsulfur within the ring or oxides thereof. Such heteroaryl groups canhave a single ring (e.g., pyridyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl). Additionally, the heteroatoms ofthe heteroaryl group may be oxidized, i.e., to form pyridine N-oxides or1,1-dioxo-1,2,5-thiadiazoles and the like. Preferred heteroaryls includepyridyl, pyrrolyl, indolyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl,1-oxo-1,2,5-thiadiazolyl and 1,1-dioxo-1,2,5-thiadiazolyl. The term“heteroaryl having two nitrogen atoms in the heteroaryl ring” refers toa heteroaryl group having two, and only two, nitrogen atoms in theheteroaryl ring and optionally containing 1 or 2 other heteroatoms inthe heteroaryl ring, such as oxygen or sulfur

“Substituted heteroaryl” refers to heteroaryl groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy; alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andamino groups on the substituted aryl blocked by conventional blockinggroups such as Boc, Cbz, formyl, and the like or substituted with—SO₂NRR where R is hydrogen or alkyl.

“Heteroaryloxy” refers to the group —O-heteroaryl and “substitutedheteroaryloxy” refers to the group —O-substituted heteroaryl.

“Heterocycle” or “heterocyclic” refers to a saturated or unsaturatedgroup having a single ring or multiple condensed rings, from 1 to 10carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfuror oxygen within the ring wherein, in fused ring systems, one or more ofthe rings can be aryl or heteroaryl.

“Substituted heterocyclic” refers to heterocycle groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O), —NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O), —NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylaminO, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andsubstituted alkynyl groups having amino groups blocked by conventionalblocking groups such as Boc, Cbz, formyl, and the like oralkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

“Heterocyclyloxy” refers to the group —O-heterocyclic and “substitutedheterocyclyloxy” refers to the group —O-substituted heterocyclic.

“Thiol” refers to the group —SH.

“Thioalkyl” refers to the groups —S-alkyl

“Substituted thioalkyl” refers to the group —S-substituted alkyl.

“Thiocycloalkyl” refers to the groups —S-cycloalkyl.

“Substituted thiocycloalkyl” refers to the group —S-substitutedcycloalkyl.

“Thioaryl” refers to the group —S-aryl and “substituted thioaryl” refersto the group —S-substituted aryl.

“Thioheteroaryl” refers to the group —S-heteroaryl and “substitutedthioheteroaryl” refers to the group —S-substituted heteroaryl.

“Thioheterocyclic” refers to the group —S-heterocyclic and “substitutedthioheterocyclic” refers to the group —S-substituted heterocyclic.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound of Formula I which salts are derived from a varietyof organic and inorganic counter ions well known in the art and include,by way of example only, sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium, and the like; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,oxalate and the like.

Compound Preparation

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts, Protecting Groups in OrganicSynthesis, Second. Edition, Wiley, New York, 1991, and references citedtherein.

Furthermore, the compounds of this invention will typically contain oneor more chiral centers. Accordingly, if desired, such compounds can beprepared or isolated as pure stereoisomers, i.e., as individualenantiomers or diastereomers, or as stereoisomer-enriched mixtures. Allsuch stereoisomers (and enriched mixtures) are included within the scopeof this invention, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents and the like.

In a preferred method of synthesis, the compounds of this invention areprepared by coupling an amino acid derivative of the formula:

where R³ and R^(3′) are as defined herein and P¹ is a carboxylic acidprotecting group (such as an alkyl group, i.e. methyl, ethyl and thelike), with a suitably functionalized heteroaryl or heterocyclicintermediate. For example, such coupling reactions may be performed bydisplacing a leaving group, such as chloro, bromo, iodo, tosyl and thelike, from the heteroaryl or heterocyclic intermediate with the aminogroup of the amino acid derivative; or by reductive alkylation of theamino group of amino acid derivative with a carbonyl-functionalizedintermediate. Such coupling reactions are well-known to those skilled inthe art.

By way of illustration, the synthesis of a representative compound offormula I is shown in Scheme 1.

As shown in Scheme 1,5-nitrouracil, 1, (commercially available fromAldrich Chemical Company, Milwaukee, Wis. USA) is treated withphosphorus oxychloride and N,N-dimethylaniline according to theprocedure described in Whittaker, J. Chem. Soc. 1951, 1565 to give1,3-dichloro-4-nitropyrimidine, 2.

1,3-Dichloro-4-nitropyrimidine, 2, is then reacted with about one molarequivalent of an amino acid derivative of the formula: H₂N—CH(R³C(O)Xwhere R³ and X are as defined herein or X is —OP¹ where P¹ is acarboxylic acid protecting group, in the presence of a trialkylamine,such as diisopropylethylamine (DIEA). Typically, this reaction isconducted in an inert diluent, such as dichloromethane, at a temperatureranging from about 0° C. to about 10° C. for about 5 min. to about 6hours to afford intermediate 3.

The nitro group of intermediate 3 is then reduced using a conventionalreducing agent, such as hydrogen and a palladium on carbon catalyst.When hydrogen and palladium on carbon are employed as the reducingagent, the chloro group of intermediate 3 is also removed. This reactionis typically conducted by contacting 3 with a Degussa-type palladium oncarbon catalyst (typically 20%) and excess sodium bicarbonate in aninert diluent, such as methanol, under hydrogen (typically about 55 psi)for about 12 to 36 hours at ambient temperature to afford aminointermediate 4.

Amino intermediate 4 is then reacted with a sulfonyl chloride of theformula: R⁵—S(O)₂—Cl, where R⁵ is as defined herein, to providesulfonamide intermediate 5. This reaction is typically conducted byreacting the amino intermediate 4 with at least one equivalent,preferably about 1.1 to about 2 equivalents, of the sulfonyl chloride inan inert diluent such as dichloromethane and the like. Generally, thereaction is conducted at a temperature ranging from about −70° C. toabout 40° C. for about 1 to about 24 hours. Preferably, this reaction isconducted in the presence of a suitable base to scavenge the acidgenerated during the reaction. Suitable bases include, by way ofexample, tertiary amines, such as triethylamine, diisopropylethylamine,N-methylmorpholine and the like. Alternatively, the reaction can beconducted under Schotten-Baumann-type conditions using aqueous alkali,such as sodium hydroxide and the like, as the base. Upon completion ofthe reaction, the resulting sulfonamide 5 is recovered by conventionalmethods including neutralization, extraction, precipitation,chromatography, filtration, and the like.

Other heteroaryl intermediates may also be employed in the abovedescribed reactions including, but not limited to,2-chloro-3-nitropyrazine (J. Med. Chem. 1984, 27, 1634);4-chloro-5-nitroimidazole (J. Chem. Soc. 1930, 268); and the like.

The amino acid derivatives employed in the above reactions are eitherknown compounds or compounds that can be prepared from known compoundsby conventional synthetic procedures. For example, amino acidderivatives can be prepared by C-alkylating commercially availablediethyl 2-acetamidomalonate (Aldrich, Milwaukee, Wis., USA) with analkyl or substituted alkyl halide. This reaction is typically conductedby treating the diethyl 2-acetamidomalonate with at least one equivalentof sodium ethoxide and at least one equivalent of an alkyl orsubstituted alkyl halide in refluxing ethanol for about 6 to about 12hours. The resulting C-alkylated malonate is then deacetylated,hydrolyzed and decarboxylated by heating in aqueous hydrochloric acid atreflux for about 6 to about 12 hours to provide the amino acid,typically as the hydrochloride salt.

Examples of amino acid derivatives suitable for use in the abovereactions include, but are not limited to, L-alanine methyl ester,L-isoleucine methyl ester, L-leucine methyl ester, L-valine methylester, β-tert-butyl-L-aspartic acid methyl ester, L-asparaginetert-butyl ester, εBoc-L-lysine methyl ester, εCbz-L-lysine methylester, γ-tert-butyl-L-glutamic acid methyl ester, L-glutamine tert-butylester, L-(N-methyl)histidine methyl ester, L-(N-benzyl)histidine methylester, L-methionine methyl ester, L-(O-benzyl)serine methyl ester,L-tryptophan methyl ester, L-phenylalanine methyl ester, L-phenylalanineisopropyl ester, L-phenylalanine benzyl ester, L-phenylalaninamide,N-methyl-L-phenylalanine benzyl ester, 3-carboxy-D,L-phenylalaninemethyl ester, 4-carboxy-D,L-phenylalanine methyl ester,L-4-chlorophenylalanine methyl ester,L-4-(3-dimethylaminopropyloxy)-phenylalanine methyl ester,L-4-iodophenylalanine methyl ester, L-3,4-methylenedioxyphenylalaninemethyl ester, L-3,4-ethylenedioxyphenylalanine methyl ester,L-4-nitrophenylalanine methyl ester, L-tyrosine methyl ester,D,L-homophenylalanine methyl ester, L-(O-methyl)tyrosine methyl ester,L-(O-tert-butyl)tyrosine methyl ester, L-(O-benzyl)tyrosine methylester, L-3,5-diiodotyrosine methyl ester, L-3-iodotyrosine methyl ester,β-(1-naphthyl)-L-alanine methyl ester, β-(2-naphthyl)-L-alanine methylester, β-(2-thienyl)-L-alanine methyl ester, β-cyclohexyl-L-alaninemethyl ester, β-(2-pyridyl)-L-alanine methyl ester,β-(3-pyridyl)-L-alanine methyl ester, β-(4-pyridyl)-L-alanine methylester, β-(2-thiazolyl)-D,L-alanine methyl ester,β-(1,2,4-triazol-3-yl)-D,L-alanine methyl ester, and the like. Ifdesired, of course, other esters or amides of the above-describedcompounds may also be employed.

Additionally, α-hydroxy and α-thio carboxylic acids may also be employedin the above-described reactions. Such compounds are well-known in theart and are either commercially available or may be prepared fromcommercially available starting materials using conventional reagentsand reaction conditions.

The sulfonyl chlorides employed in the above reaction are also eitherknown compounds or compounds that can be prepared from known compoundsby conventional synthetic procedures. Such compounds are typicallyprepared from the corresponding sulfonic acid, i.e., from compounds ofthe formula R⁵—SO₃H where R⁵ is as defined above, using phosphoroustrichloride and phosphorous pentachloride. This reaction is generallyconducted by contacting the sulfonic acid with about 2 to 5 molarequivalents of phosphorous trichloride and phosphorous pentachloride,either neat or in an inert solvent, such as dichloromethane, attemperature in the range of about 0° C. to about 80° C. for about 1 toabout 48 hours to afford the sulfonyl chloride. Alternatively, thesulfonyl chloride can be prepared from the corresponding thiol compound,i.e., from compounds of the formula R⁵—SH where R⁵ is as defined herein,by treating the thiol with chlorine (Cl₂) and water under conventionalreaction conditions.

Examples of sulfonyl chlorides suitable for use in this inventioninclude, but are not limited to, methanesulfonyl chloride,2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonylchloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonylchloride, p-toluenesulfonyl chloride, α-toluenesulfonyl chloride,4-acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride,4-tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride,2-carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride,3,4-dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonylchloride, 3,4-dimethoxybenzenesulfonyl chloride,3,5-ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonylchloride, 4-methoxybenzenesulfonyl chloride,2-methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulfonylchloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonylchloride, 4-trifluoromethylbenzenesulfonyl chloride,4-trifluoromethoxybenzenesulfonyl chloride,2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonylchloride, 2-thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonylchloride, 2,5-dichloro-4-thiophenesulfonyl chloride, 2-thiazolesulfonylchloride, 2-methyl-4-thiazolesulfonyl chloride,1-methyl-4-imidazolesulfonyl chloride, 1-methyl-4-pyrazolesulfonylchloride, 5-chloro-1,3-dimethyl-4-pyrazolesulfonyl chloride,3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride and the like.If desired, a sulfonyl fluoride, sulfonyl bromide or sulfonic acidanhydride may be used in place of the sulfonyl chloride in the abovereaction to form the sulfonamide intermediate 5.

If desired, sulfonamide intermediate 5 can be alkylated at thesulfonamide nitrogen atom to provide compound 6. For example, 5 can becontacted with excess diazomethane (generated, for example, using1-methyl-3-nitro-1-nitrosoguanidine and sodium hydroxide) to afford 6where R⁶ is methyl. Other conventional alkylation procedures andreagents may also be employed to prepare various compounds of thisinvention.

In another preferred embodiment, compounds of this invention may beprepared by displacement of a leaving group as shown in Scheme 2:

where R³, Q and X are as defined herein; A′ is heteroaryl, substitutedheteroaryl, heterocyclic or substituted heterocyclic containing twonitrogen atoms in the heteroaryl or heterocyclic ring; and L¹ is aleaving group, such as chloro, bromo, iodo, sulfonate ester and thelike.

Typically, this reaction is conducted by combining approximatelystoichiometric equivalents of 7 and 8 in a suitable inert diluent suchas water, dimethylsulfoxide (DMSO) and the like, with an excess of asuitable base such as sodium bicarbonate, sodium hydroxide, etc. toscavenge the acid generated by the reaction. The reaction is preferablyconducted at from about 25° C. to about 100° C. until reactioncompletion which typically occurs within 1 to about 24 hours. Thisreaction is further described in U.S. Pat. No. 3,598,859, which isincorporated herein by reference in its entirety. Upon reactioncompletion, the product 9 is recovered by conventional methods includingprecipitation, chromatography, filtration and the like.

In still another alternative embodiment, compounds of this invention inwhich Q is NR⁴ can be prepared by reductive amination of a suitable2-oxocarboxylic acid ester, 10, such as a pyruvate ester, as shown inScheme 3:

where A′, R³ and X are as defined herein.

Generally, this reaction is conducted by combining equamolar amounts of10 and 11 in an inert diluent such as methanol, ethanol and the likeunder conditions which provide for imine formation (not shown). Theimine formed is then reduced under conventional conditions by a suitablereducing agent such as sodium cyanoborohydride, H₂/palladium on carbonand the like to form the product 12. In a particularly preferredembodiment, the reducing agent is H₂/palladium on carbon which isincorporated into the initial reaction medium thereby permitting iminereduction in situ in a one pot procedure to provide 12. The reaction ispreferably conducted at from about 20° C. to about 80° C. at a pressureof from 1 to 10 atmospheres until reaction completion which typicallyoccurs within 1 to about 24 hours. Upon reaction completion, the product12 is recovered by conventional methods including chromatography,filtration and the like.

Alternatively, certain compounds of this invention can be prepared via arhodium-catalyzed insertion reaction as shown in Scheme 4:

where A″ is heteroaryl or substituted heteroaryl containing two nitrogenatoms in the heteroaryl ring, and R³ and X (preferably alkoxy) are asdefined herein. Typically, this reaction is conducted using rhodiumacetate dimer, Rh₂(OAc)₄, in an inert diluent such as toluene at atemperature ranging from about 25° C. to about 80° C. for about 1 to 12hours to afford 15. This reaction is described further in B. R. Henkeet. al., J. Med. Chem. 1998, 41, 5020-5036 and references cited therein.

Similarly, certain compounds of this invention can be prepared by thecopper-catalyzed coupling reaction shown in Scheme 5:

where A″ is as defined herein, X³ is halogen, such as chloro, bromo oriodo (preferably iodo), and R³ and X (preferably alkoxy) are as definedherein. Typically, this reaction is conducted using copper iodide (CuI)and potassium carbonate in an inert diluent such as N,N-dimethylacetamide (DMA) at a temperature ranging from about 60° C. to about 120°C. for about 12 to 36 hours to afford 15. This reaction is describedfurther in D. Ma et. al., J. Am. Chem. Soc. 1998, 120, 12459-12467 andreferences cited therein.

For ease of synthesis, the compounds of this invention are typicallyprepared as an ester, i.e., where X is an alkoxy or substituted alkoxygroup and the like. If desired, the ester group can be hydrolysed usingconventional conditions and reagents to provide the correspondingcarboxylic acid. Typically, this reaction is conducted by treating theester with at least one equivalent of an alkali metal hydroxide, such aslithium, sodium or potassium hydroxide, in an inert diluent, such asmethanol or mixtures of methanol and water, at a temperature rangingabout 0° C. to about 24° C. for about 1 to about 12 hours.Alternatively, benzyl esters may be removed by hydrogenolysis using apalladium catalyst, such as palladium on carbon, and tert-butyl esterscan be removed using formic acid to afford the corresponding carboxylicacid.

As will be apparent to those skilled in the art, other functional groupspresent on any of the substituents of the compounds of formulas I-VIIcan be readily modified or derivatized either before or after theabove-described synthetic reactions using well-known syntheticprocedures. For example, a nitro group present on a substituent of acompound of formula I-VE or an intermediate thereof may be readilyreduced by hydrogenation in the presence of a palladium catalyst, suchas palladium on carbon, to provide the corresponding amino group. Thisreaction is typically conducted at a temperature of from about 20° C. toabout 50° C. for about 6 to about 24 hours in an inert diluent, such asmethanol. Compounds having a nitro group on the R³ and/or R^(3′)substituent can be prepared, for example, by using a4-nitrophenylalanine derivative and the like in the above-describedcoupling reactions.

Similarly, a pyridyl group can be hydrogenated in the presence of aplatinum catalyst, such as platinum oxide, in an acidic diluent toprovide the corresponding piperidinyl analogue. Generally, this reactionis conducted by treating the pyridine compound with hydrogen at apressure ranging from about 20 psi to about 60 psi, preferably about 40psi, in the presence of the catalyst at a temperature of about 20° C. toabout 50° C. for about 2 to about 24 hours in an acidic diluent, such asa mixture of methanol and aqueous hydrochloric acid.

Additionally, when the R³ and/or R^(3′) substituent of a compound offormula I-VE or an intermediate thereof contains a primary or secondaryamino group, such amino groups can be further derivatized either beforeor after the above coupling reactions to provide, by way of example,amides, sulfonamides, ureas, thioureas, carbamates, secondary ortertiary amines and the like. Compounds having a primary amino group onthe R³ and/or R^(3′) substituent may be prepared, for example, byreduction of the corresponding nitro compound as described above.

By way of illustration, a compound of formula or an intermediate thereofhaving a substituent containing a primary or secondary amino group, suchas where R³ is a (4-aminophenyl)methyl group, can be readily N-acylatedusing conventional acylating reagents and conditions to provide thecorresponding amide. This acylation reaction is typically conducted bytreating the amino compound with at least one equivalent, preferablyabout 1.1 to about 1.2 equivalents, of a carboxylic acid in the presenceof a coupling reagent such as a carbodiimide, BOP reagent(benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphonate) and the like, in an inert diluent, such asdichloromethane, chloroform, acetonitrile, tetrahydrofuran,N,N-dimethylformamide and the like, at a temperature ranging from about0° C. to about 37° C. for about 4 to about 24 hours. Preferably, apromoter, such as N-hydroxysuccinimide, 1-hydroxy-benzotriazole and thelike, is used to facilitate the acylation reaction. Examples ofcarboxylic acids suitable for use in this reaction include, but are notlimited to, N-tert-butyloxycarbonylglycine,N-tert-butyloxycarbonyl-L-phenylalanine,N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid,N-tert-butyloxycarbonylisonipecotic acid, N-methylisonipecotic acid,N-tert-butyloxycarbonylnipecotic acid,N-tert-butyloxycarbonyl-L-tetrahydroisoquinoline-3-carboxylic acid,N-(toluene-4-sulfonyl)-L-proline and the like.

Alternatively, a compound of formula I-VII or an intermediate thereofcontaining a primary or secondary amino group can be N-acylated using anacyl halide or a carboxylic acid anhydride to form the correspondingamide. This reaction is typically conducted by contacting the aminocompound with at least one equivalent, preferably about 1.1 to about 1.2equivalents, of the acyl halide or carboxylic acid anhydride in an inertdiluent, such as dichloromethane, at a temperature ranging from about−70° C. to about 40° C. for about 1 to about 24 hours. If desired, anacylation catalyst such as 4-(N,N-dimethylamino)pyridine may be used topromote the acylation reaction. The acylation reaction is preferablyconducted in the presence of a suitable base to scavenge the acidgenerated during the reaction. Suitable bases include, by way ofexample, tertiary amines, such as triethylamine, diisopropylethylamine,N-methylmorpholine and the like. Alternatively, the reaction can beconducted under Schotten-Baumann-type conditions using aqueous alkali,such as sodium hydroxide and the like.

Examples of acyl halides and carboxylic acid anhydrides suitable for usein this reaction include, but are not limited to, 2-methylpropionylchloride, trimethylacetyl chloride, phenylacetyl chloride, benzoylchloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride,2-trifluoro-methylbenzoyl chloride, isonicotinoyl chloride, nicotinoylchloride, picolinoyl chloride, acetic anhydride, succinic anhydride, andthe like. Carbamyl chlorides, such as N,N-dimethylcarbamyl chloride,N,N-diethylcarbamyl chloride and the like, can also be used in thisreaction to provide ureas. Similarly, dicarbonates, such asdi-tert-butyl dicarbonate, may be employed to provide carbamates.

In a similar manner, a compound of formula I-VII or an intermediatethereof containing a primary or secondary amino group may beN-sulfonated to form a sulfonamide using a sulfonyl halide or a sulfonicacid anhydride. Sulfonyl halides and sulfonic acid anhydrides suitablefor use in this reaction include, but are not limited to,methanesulfonyl chloride, chloromethanesulfonyl chloride,p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and thelike. Similarly, sulfamoyl chlorides, such as dimethylsulfamoylchloride, can be used to provide sulfamides (e.g., >N—SO₂—N<).

Additionally, a primary and secondary amino group present on asubstituent of a compound of formula I-VII or an intermediate thereofcan be reacted with an isocyanate or a thioisocyanate to give a urea orthiourea, respectively. This reaction is typically conducted bycontacting the amino compound with at least one equivalent, preferablyabout 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanatein an inert diluent, such as toluene and the like, at a temperatureranging from about 24° C. to about 37° C. for about 12 to about 24hours. The isocyanates and thioisocyanates used in this reaction arecommercially available or can be prepared from commercially availablecompounds using well-known synthetic procedures. For example,isocyanates and thioisocyanates are readily prepared by reacting theappropriate amine with phosgene or thiophosgene. Examples of isocyanatesand thioisocyanates suitable for use in this reaction include, but arenot limited to, ethyl isocyanate, n-propyl isocyanate, 4-cyanophenylisocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methylthioisocyanate, ethyl thioisocyanate, 2-phenylethyl thioisocyanate,3-phenylpropyl thioisocyanate, 3-(N,N-diethylamino)propylthioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridylthioisocyanate; fluorescein isothiocyanate (isomer I) and the like.

Furthermore, when a compound of formula I-VII or an intermediate thereofcontains a primary or secondary amino group, the amino group can bereductively alkylated using aldehydes or ketones to form a secondary ortertiary amino group. This reaction is typically conducted by contactingthe amino compound with at least one equivalent, preferably about 1.1 toabout 1.5 equivalents, of an aldehyde or ketone and at least oneequivalent based on the amino compound of a metal hydride reducingagent, such as sodium cyanoborohydride, in an inert diluent, such asmethanol, tetrahydrofuran, mixtures thereof and the like, at atemperature ranging from about 0° C. to about 50° C. for about 1 toabout 72 hours. Aldehydes and ketones suitable for use in this reactioninclude, by way of example, benzaldehyde, 4-chlorobenzaldehyde,valeraldehyde and the like.

In a similar manner, when a compound of formula I-VII or an intermediatethereof has a substituent containing a hydroxyl group, the hydroxylgroup can be further modified or derivatized either before or after theabove coupling reactions to provide, by way of example, ethers,carbamates and the like. Compounds having a hydroxyl group on the R³substituent, for example, can be prepared using an amino acid derivativederived from tyrosine and the like in the above-described reactions.

By way of example, a compound of formula I-VII or an intermediatethereof having a substituent containing a hydroxyl group, such as whereR³ is a (4-hydroxyphenyl)methyl group, can be readily O-alkylated toform ethers. This O-alkylation reaction is typically conducted bycontacting the hydroxy compound with a suitable alkali or alkaline earthmetal base, such as potassium carbonate, in an inert diluent, such asacetone, 2-butanone and the like, to form the alkali or alkaline earthmetal salt of the hydroxyl group. This salt is generally not isolated,but is reacted in situ with at least one equivalent of an alkyl orsubstituted alkyl halide or sulfonate, such as an alkyl chloride,bromide, iodide, mesylate or tosylate, to afford the ether. Generally,this reaction is conducted at a temperature ranging from about 60° C. toabout 150° C. for about 24 to about 72 hours. Preferably, a catalyticamount of sodium or potassium iodide is added to the reaction mixturewhen an alkyl chloride or bromide is employed in the reaction.

Examples of alkyl or substituted alkyl halides and sulfonates suitablefor use in this reaction include, but are not limited to, tert-butylbromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethylα-bromophenylacetate, 2-(N-ethyl-N-phenylamino)ethyl chloride,2-(N,N-ethylamino)ethyl chloride, 2-(N,N-diisopropylamino)ethylchloride, 2-(N,N-dibenzylamino)ethyl chloride, 3-(N,N-ethylamino)propylchloride, 3-(N-benzyl-N-methylamino)propyl chloride,N-(2-chloroethyl)morpholine, 2-(hexamethyleneimino)ethyl chloride;3-(N-methylpiperazine)propyl chloride,1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine,2-(4-hydroxy-4-phenylpiperidine)ethyl chloride,N-tert-butyloxycarbonyl-3-piperidinemethyl tosylate, and the like.

Alternatively, a hydroxyl group present on a substituent of a compoundof formula I-VII or an intermediate thereof can be O-alkylating usingthe Mitsunobu reaction. In this reaction, an alcohol, such as3-(N,N-dimethylamino)-1-propanol and the like, is reacted with about 1.0to about 1.3 equivalents of triphenylphosphine and about 1.0 to about1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such astetrahydrofuran, at a temperature ranging from about −10° C. to about 5°C. for about 0.25 to about 1 hour. About 1.0 to about 1.3 equivalents ofa hydroxy compound, such as N-tert-butyltyrosine methyl ester, is thenadded and the reaction mixture is stirred at a temperature of about 0°C. to about 30° C. for about 2 to about 48 hours to provide theO-alkylated product.

In a similar manner, a compound of formula I-VII or an intermediatethereof containing an aryl hydroxy group can be reacted with an aryliodide to provide a diaryl ether. Generally, this reaction is conductedby forming the alkali metal salt of the hydroxyl group using a suitablebase, such as sodium hydride, in an inert diluent such as xylenes at atemperature of about −25° C. to about 10° C. The salt is then treatedwith about 1.1 to about 1.5 equivalents of cuprous bromide dimethylsulfide complex at a temperature ranging from about 10° C. to about 30°C. for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5equivalents of an aryl iodide, such as sodium 2-iodobenzoate and thelike. The reaction is then heated to about 70° C. to about 150° C. forabout 2 to about 24 hours to provide the diaryl ether.

Additionally, a hydroxy-containing compound can also be readilyderivatized to form a carbamate. In one method for preparing suchcarbamates, a hydroxy compound of formula I-VII or an intermediatethereof is contacted with about 1.0 to about 1.2 equivalents of4-nitrophenyl chloroformate in an inert diluent, such asdichloromethane, at a temperature ranging from about −25° C. to about 0°C. for about 0.5 to about 2.0 hours. Treatment of the resultingcarbonate with an excess, preferably about 2 to about 5 equivalents, ofa trialkylamine, such as triethylamine, for about 0.5 to 2 hours,followed by about 1.0 to about 1.5 equivalents of a primary or secondaryamine provides the carbamate. Examples of amines suitable for using inthis reaction include, but are not limited to, piperazine,1-methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine,pyrrolidine, piperidine and the like.

Alternatively, in another method for preparing carbamates, ahydroxy-containing compound is contacted with about 1.0 to about 1.5equivalents of a carbamyl chloride in an inert diluent, such asdichloromethane, at a temperature ranging from about 25° C. to about 70°C. for about 2 to about 72 hours. Typically, this reaction is conductedin the presence of a suitable base to scavenge the acid generated duringthe reaction. Suitable bases include, by way of example, tertiaryamines, such as triethylamine, diisopropylethylamine, N-methylmorpholineand the like. Additionally, at least one equivalent (based on thehydroxy compound) of 4-(N,N-dimethylamino)pyridine is preferably addedto the reaction mixture to facilitate the reaction. Examples of carbamylchlorides suitable for use in this reaction include, by way of example,dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.

Likewise, when a compound of formula I-VE or an intermediate thereofcontains a primary or secondary hydroxyl group, such hydroxyl groups canbe readily converted into a leaving group and displaced to form, forexample, amines, sulfides and fluorides. Generally, when a chiralcompound is employed in these reactions, the stereochemistry at thecarbon atom attached to the derivatized hydroxyl group is typicallyinverted.

These reactions are typically conducted by first converting the hydroxylgroup into a leaving group, such as a tosylate, by treatment of thehydroxy compound with at least one equivalent of a sulfonyl halide, suchas p-toluenesulfonyl chloride and the like, in pyridine. This reactionis generally conducted at a temperature of from about 0° C. to about 70°C. for about 1 to about 48 hours. The resulting tosylate can then bereadily displaced with sodium azide, for example, by contacting thetosylate with at least one equivalent of sodium azide in an inertdiluent, such as a mixture of N,N-dimethylformamide and water, at atemperature ranging from about 0° C. to about 37° C. for about 1 toabout 12 hours to provide the corresponding azido compound. The azidogroup can then be reduced by, for example, hydrogenation using apalladium on carbon catalyst to provide the amino (—NH₂) compound.

Similarly, a tosylate group can be readily displaced by a thiol to forma sulfide. This reaction is typically conducted by contacting thetosylate with at least one equivalent of a thiol, such as thiophenol, inthe presence of a suitable base, such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in an inert diluent, such asN,N-dimethylformamide, at a temperature of from about 0° C. to about 37°C. for about 1 to about 12 hours to provide the sulfide. Additionally,treatment of a tosylate with morpholinosulfur trifluoride in an inertdiluent, such as dichloromethane, at a temperature ranging from about 0°C. to about 37° C. for about 12 to about 24 hours affords thecorresponding fluoro compound.

Furthermore, a compound of formula I-VII or an intermediate thereofhaving a substituent containing an iodoaryl group, for example, when R³is a (4-iodophenyl)methyl group, can be readily converted either beforeor after the above coupling reactions into a biaryl compound. Typically,this reaction is conducted by treating the iodoaryl compound with about1.1 to about 2 equivalents of an arylzinc iodide, such as2-(methoxycarbonyl)phenylzinc iodide, in the presence of a palladiumcatalyst, such as palladium tetra(triphenylphosphine), in an inertdiluent, such as tetrahydrofuran, at a temperature ranging from about24° C. to about 30° C. until reaction completion. This reaction isfurther described, for example, in Rieke, J. Org. Chem. 1991, 56, 1445.Additional methods for preparing biaryl derivatives are disclosed inInternational Publication Number WO 98/53817, published Dec. 3, 1998,the disclosure of which is incorporated herein by reference in itsentirety.

In some cases, the compounds of formula I-VII or intermediates thereofmay contain substituents having one or more sulfur atoms. When present,such sulfur atoms can be oxidized either before or after the abovecoupling reactions to provide a sulfoxide or sulfone compound usingconventional reagents and reaction conditions. Suitable reagents foroxidizing a sulfide compound to a sulfoxide include, by way of example,hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA), sodium periodateand the like. The oxidation reaction is typically conducted bycontacting the sulfide compound with about 0.95 to about 1.1 equivalentsof the oxidizing reagent in an inert diluent, such as dichloromethane,at a temperature ranging from about −50° C. to about 75° C. for about 1to about 24 hours. The resulting sulfoxide can then be further oxidizedto the corresponding sulfone by contacting the sulfoxide with at leastone additional equivalent of an oxidizing reagent, such as hydrogenperoxide, MCPBA, potassium permanganate and the like. Alternatively, thesulfone can be prepared directly by contacting the sulfide with at leasttwo equivalents, and preferably an excess, of the oxidizing reagent.Such reactions are described further in March, “Advanced OrganicChemistry”, 4th Ed., pp. 1201-1202, Wiley Publisher, 1992.

Other procedures and reaction conditions for preparing the compounds ofthis invention are described in the examples set forth below.Additionally, other procedures for preparing compounds useful in certainaspects of this invention are disclosed in U.S. Ser. No. ______, filedon even date herewith, entitled “Compounds Which Inhibit LeucocyteAdhesion Mediated by VLA-4” (Attorney Docket No. 002010-525); thedisclosure of which is incorporated herein by reference in its entirety.

Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds of this invention areusually administered in the form of pharmaceutical compositions. Thesecompounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal. These compounds are effective as both injectable and oralcompositions. Such compositions are prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of formula I-VIIabove associated with pharmaceutically acceptable carriers. In makingthe compositions of this invention, the active ingredient is usuallymixed with an excipient, diluted by an excipient or enclosed within sucha carrier which can be in the form of a capsule, sachet, paper or othercontainer. The excipient employed is typically an excipient suitable foradministration to human subjects or other mammals. When the excipientserves as a diluent, it can be a solid, semi-solid, or liquid material,which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, suppositories, sterile injectablesolutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated M a unit dosage form, eachdosage containing from about 5 to about 100 mg, more usually about 10 toabout 30 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably, orally or nasally, from devices which deliver theformulation in an appropriate manner.

The following formulation examples illustrate the pharmaceuticalcompositions of the present invention.

Formulation Example 1

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

Formulation Example 2

A tablet formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

Formulation Example 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active mixture is mixed with the lactose and the mixture is added toa dry powder inhaling appliance.

Formulation Example 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone  4.0 mg (as 10%solution in water) Sodium carboxymethyl starch  4.5 mg Magnesiumstearate  0.5 mg Talc  1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinyl-pyrrolidone is mixed with the resultant powders, which arethen passed through a 16 mesh U.S. sieve. The granules so produced aredried at 50° to 60° C. and passed through a 16 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 30 mesh U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yield tabletseach weighing 150 mg.

Formulation Example 5

Capsules, each containing 40 mg of medicament are made as follows:

Quantity Ingredient (mg/capsule) Active Ingredient  40.0 mg Starch 109.0mg Magnesium stearate  1.0 mg Total 150.0 mg

The active ingredient, cellulose, starch, an magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

Formulation Example 6

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 7

Suspensions, each containing 50 mg of medicament per 5.0 ml dose aremade as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) 50.0 mg Microcrystalline cellulose (89%)Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 ml

The medicament, sucrose and xanthan gum are blended, passed through aNo. 10 mesh U.S. sieve, and then mixed with a previously made solutionof the microcrystalline cellulose and sodium carboxymethyl cellulose inwater. The sodium benzoate, flavor, and color are diluted with some ofthe water and added with stirring. Sufficient water is then added toproduce the required volume.

Formulation Example 8

Quantity Ingredient (mg/capsule) Active Ingredient  15.0 mg Starch 407.0mg Magnesium stearate  3.0 mg Total 425.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 560 mg quantities.

Formulation Example 9

An intravenous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 250.0 mg Isotonic saline  1000 ml

Formulation Example 10

A topical formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g LiquidParaffin 20 g White Soft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Direct or indirect placement techniques may be used when it is desirableor necessary to introduce the pharmaceutical composition to the brain.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system used for the transport ofbiological factors to specific anatomical regions of the body isdescribed in U.S. Pat. No. 5,011,472 which is herein incorporated byreference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs. Latentiationis generally achieved through blocking of the hydroxy, carbonyl,sulfate, and primary amine groups present on the drug to render the drugmore lipid soluble and amenable to transportation across the blood-brainbarrier. Alternatively, the delivery of hydrophilic drugs may beenhanced by intra-arterial infusion of hypertonic solutions which cantransiently open the blood-brain barrier.

Utility

The compounds of this invention can be employed to bind VLA-4 (α₄β₁integrin) in biological samples, i.e., the compounds bind VLA-4 with anIC₅₀ of 15 μM or less in a competitive binding assay as describedherein. Accordingly, these compounds have utility in, for example,assaying such samples for VLA-4. In such assays, the compounds can bebound to a solid support and the VLA-4 sample added thereto. The amountof VLA-4 in the sample can be determined by conventional methods such asuse of a sandwich ELISA assay. Althernatively, labeled VLA-4 can be usedin a competitive assay to measure for the presence of VLA-4 in thesample. Other suitable assays are well known in the art.

In addition, certain of the compounds of this invention inhibit, invivo, adhesion of leukocytes to endothelial cells mediated by VLA-4 bycompetitive binding to VLA-4. Accordingly, the compounds of thisinvention can be used in the treatment of diseases mediated by VLA-4 orleucocyte adhesion. Such diseases include inflammatory diseases inmammalian patients such as asthma, Alzheimer's disease, atherosclerosis,AIDS dementia, diabetes (including acute juvenile onset diabetes),inflammatory bowel disease (including ulcerative colitis and Crohn'sdisease), multiple sclerosis; rheumatoid arthritis, tissuetransplantation, tumor metastasis, meningitis, encephalitis, stroke, andother cerebral traumas, nephritis, retinitis, atopic dermatitis,psoriasis, myocardial ischemia and acute leukocyte-mediated lung injurysuch as that which occurs in adult respiratory distress syndrome.

The biological activity of the compounds identified above may be assayedin a variety of systems. For example, a compound can be immobilized on asolid surface and adhesion of cells expressing VLA-4 can be measured.Using such formats, large numbers of compounds can be screened. Cellssuitable for this assay include any leukocytes known to express VLA-4such as T cells, B cells, monocytes, eosinophils, and basophils. Anumber of leukocyte cell lines can also be used, examples include Jurkatand U937.

The test compounds can also be tested for the ability to competitivelyinhibit binding between VLA-4 and VCAM-1, or between VLA-4 and a labeledcompound known to bind VLA-4 such as a compound of this invention orantibodies to VLA-4. In these assays, the VCAM-1 can be immobilized on asolid surface. VCAM-1 may also be expressed as a recombinant fusionprotein having an Ig tail (e.g., IgG) so that binding to VLA-4 may bedetected in an immunoassay. Alternatively, VCAM-1 expressing cells, suchas activated endothelial cells or VCAM-1 transfected fibroblasts can beused. For assays to measure the ability to block adhesion to brainendothelial cells, the assays described in International PatentApplication Publication No. WO 91/05038 are particularly preferred. Thisapplication is incorporated herein by reference in its entirety.

Many assay formats employ labelled assay components. The labellingsystems can be in a variety of forms. The label may be coupled directlyor indirectly to the desired component of the assay according to methodswell known in the art. A wide variety of labels may be used. Thecomponent may be labelled by any one of several methods. The most commonmethod of detection is the use of autoradiography with ³H, ¹²⁵I, ³⁵S,¹⁴C, or ³²P labelled compounds or the like. Non-radioactive labelsinclude ligands which bind to labelled antibodies, fluorophores,chemiluminescent agents, enzymes and antibodies which can serve asspecific binding pair members for a labelled ligand. The choice of labeldepends on sensitivity required, ease of conjugation with the compound,stability requirements, and available instrumentation.

Appropriate in vivo models for demonstrating efficacy in treatinginflammatory responses include EAE (experimental autoimmuneencephalomyelitis) in mice, rats, guinea pigs or primates, as well asother inflammatory models dependent upon α4 integrins.

Compounds having the desired biological activity may be modified asnecessary to provide desired properties such as improved pharmacologicalproperties (e.g., in vivo stability, bio-availability), or the abilityto be detected in diagnostic applications. Stability can be assayed in avariety of ways such as by measuring the half-life of the proteinsduring incubation with peptidases or human plasma or serum. A number ofsuch protein stability assays have been described (see, e.g., Verhoef etal., Eur. J. Drug Metab. Pharmacokinet., 1990, 15(2):83-93).

For diagnostic purposes, a wide variety of labels may be linked to thecompounds, which may provide, directly or indirectly, a detectablesignal. Thus, the compounds of the subject invention may be modified ina variety of ways for a variety of end purposes while still retainingbiological activity. In addition, various reactive sites may beintroduced at the terminus for linking to particles, solid substrates,macromolecules, or the like.

Labeled compounds can be used in a variety of in vivo or in vitroapplications. A wide variety of labels may be employed, such asradionuclides (e.g., gamma-emitting radioisotopes such as technetium-99or indium-111), fluorescers (e.g., fluorescein), enzymes, enzymesubstrates, enzyme cofactors, enzyme inhibitors, chemiluminescentcompounds, bioluminescent compounds, and the like. Those of ordinaryskill in the art will know of other suitable labels for binding to thecomplexes, or will be able to ascertain such using routineexperimentation. The binding of these labels is achieved using standardtechniques common to those of ordinary skill in the art.

In vitro uses include diagnostic applications such as monitoringinflammatory responses by detecting the presence of leukocytesexpressing VLA-4. The compounds of this invention can also be used forisolating or labeling such cells. In addition, as mentioned above, thecompounds of the invention can be used to assay for potential inhibitorsof VLA-4/VCAM-1 interactions.

For in vivo diagnostic imaging to identify, e.g., sites of inflammation,radioisotopes are typically used in accordance with well knowntechniques. The radioisotopes may be bound, to the peptide eitherdirectly or indirectly using intermediate functional groups. Forinstance, chelating agents such as diethylenetriaminepentacetic acid(DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar moleculeshave been used to bind proteins to metallic ion radioisotopes.

The complexes can also be labeled with a paramagnetic isotope forpurposes of in vivo diagnosis, as in magnetic resonance imaging (MRI) orelectron spin resonance (ESR), both of which are well known. In general,any conventional method for visualizing diagnostic imaging can be used.Usually gamma- and positron-emitting radioisotopes are used for cameraimaging and paramagnetic isotopes are used for MRI. Thus, the compoundscan be used to monitor the course of amelioration of an inflammatoryresponse in an individual. By measuring the increase or decrease inlymphocytes expressing VLA-4 it is possible to determine whether aparticular therapeutic regimen aimed at ameliorating the disease iseffective.

The pharmaceutical compositions of the present invention can be used toblock or inhibit cellular adhesion associated with a number of diseasesand disorders. For instance, a number of inflammatory disorders areassociated with integrins or leukocytes. Treatable disorders include,e.g., transplantation rejection (e.g., allograft rejection), Alzheimer'sdisease, atherosclerosis, AIDS dementia, diabetes (including acutejuvenile onset diabetes), retinitis, cancer metastases, rheumatoidarthritis, acute leukocyte-mediated lung injury (e.g., adult respiratorydistress syndrome), asthma, nephritis, rand acute and chronicinflammation, including atopic dermatitis, psoriasis, myocardialischemia, and inflammatory bowel disease (including Crohn's disease andulcerative colitis). In preferred embodiments the pharmaceuticalcompositions are used to treat inflammatory brain disorders, such asmultiple sclerosis (MS), viral meningitis and encephalitis.

Inflammatory bowel disease is a collective term for two similar diseasesreferred to as Crohn's disease and ulcerative colitis. Crohn's diseaseis an idiopathic, chronic ulceroconstrictive inflammatory diseasecharacterized by sharply delimited and typically transmural involvementof all layers of the bowel wall by a granulomatous inflammatoryreaction. Any segment of the gastrointestinal tract, from the mouth tothe anus, may be involved, although the disease most commonly affectsthe terminal ileum and/or colon. Ulcerative colitis is an inflammatoryresponse limited largely to the colonic mucosa and submucosa.Lymphocytes and macrophages are numerous in lesions of inflammatorybowel disease and may contribute to inflammatory injury.

Asthma is a disease characterized by increased responsiveness of thetracheobronchial tree to various stimuli potentiating paroxysmalconstriction of the bronchial airways. The stimuli cause release ofvarious mediators of inflammation from IgE-coated mast cells includinghistamine, eosinophilic and neutrophilic chemotactic factors,leukotrines, prostaglandin and platelet activating factor. Release ofthese factors recruits basophils, eosinophils and neutrophils, whichcause inflammatory injury.

Atherosclerosis is a disease of arteries (e.g., coronary, carotid, aortaand iliac). The basic lesion, the atheroma, consists of a raised focalplaque within the intima, having a core of lipid and a covering fibrouscap. Atheromas compromise arterial blood flow and weaken affectedarteries. Myocardial and cerebral infarcts are a major consequence ofthis disease. Macrophages and leukocytes are recruited to atheromas andcontribute to inflammatory injury.

Rheumatoid arthritis is a chronic, relapsing inflammatory disease thatprimarily causes impairment and destruction of joints. Rheumatoidarthritis usually first affects the small joints of the hands and feetbut then may involve the wrists, elbows, ankles and knees. The arthritisresults from interaction of synovial cells with leukocytes thatinfiltrate from the circulation into the synovial lining of the joints.See e.g., Paul, Immunology (3d ed., Raven Press, 1993).

Another indication for the compounds of this invention is in treatmentof organ or graft rejection mediated by VLA-4. Over recent years therehas been a considerable improvement in the efficiency of surgicaltechniques for transplanting tissues and organs such as skin, kidney,liver, heart, lung, pancreas and bone marrow. Perhaps the principaloutstanding problem is the lack of satisfactory agents for inducingimmunotolerance in the recipient to the transplanted allograft or organ.When allogeneic cells or organs are transplanted into a host (i.e., thedonor and donee are different individuals from the same species), thehost immune system is likely to mount an immune response to foreignantigens in the transplant (host-versus-graft disease) leading todestruction of the transplanted tissue. CD8⁺ cells, CD4 cells andmonocytes are all involved in the rejection of transplant tissues.Compounds of this invention which bind to alpha-4 integrin are useful,inter alfa, to block alloantigen-induced immune responses in the doneethereby preventing such cells from participating in the destruction ofthe transplanted tissue or organ. See, e.g., Paul et al., TransplantInternational 9, 420-425 (1996); Georczynski et al., Immunology 87,573-580 (1996); Georcyznski et al., Transplant. Immunol. 3, 55-61(1995); Yang et al., Transplantation 60, 71-76 (1995); Anderson et al.,APMIS 102, 23-27 (1994).

A related use for compounds of this invention which bind to VLA-4 is inmodulating the immune response involved in “graft versus host” disease(GVHD). See e.g., Schlegel et al., J. Immunol. 155, 3856-3865 (1995).GVHD is a potentially fatal disease that occurs when immunologicallycompetent cells are transferred to an allogeneic recipient. In thissituation, the donor's immunocompetent cells may attack tissues in therecipient. Tissues of the skin, gut epithelia and liver are frequenttargets and may be destroyed during the course of GVHD. The diseasepresents an especially severe problem when immune tissue is beingtransplanted, such as in bone marrow transplantation; but less severeGVHD has also been reported in other cases as well, including heart andliver transplants. The therapeutic agents of the present invention areused, inter alia, to block activation of the donor T-cells therebyinterfering with their ability to lyse target cells in the host.

A further use of the compounds of this invention is inhibiting tumormetastasis. Several tumor cells have been reported to express VLA-4 andcompounds which bind VLA-4 block adhesion of such cells to endothelialcells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al.,Int. J. Cancer 60, 867-71 (1995); Freedman et al., Leuk. Lymphoma 13,47-52 (1994); Okahara et al., Cancer Res. 54, 3233-6 (1994).

A further use of the compounds of this invention is in treating multiplesclerosis. Multiple sclerosis is a progressive neurological autoimmunedisease that affects an estimated 250,000 to 350,000 people in theUnited States. Multiple sclerosis is thought to be the result of aspecific autoimmune reaction in which certain leukocytes attack andinitiate the destruction of myelin, the insulating sheath covering nervefibers. In an animal model for multiple sclerosis, murine monoclonalantibodies directed against VLA-4 have been shown to block the adhesionof leukocytes to the endothelium, and thus prevent inflammation of thecentral nervous system and subsequent paralysis in the animals¹⁶.

Pharmaceutical compositions of the invention are suitable for use in avariety of drug delivery systems. Suitable formulations for use in thepresent invention are found in Remington's Pharmaceutical Sciences, MacePublishing. Company, Philadelphia, Pa., 17th ed. (1985).

In order to enhance serum half-life, the compounds may be encapsulated,introduced into the lumen of liposomes, prepared as a colloid, or otherconventional techniques may be employed which provide an extended serumhalf-life of the compounds. A variety of methods are available forpreparing liposomes, as described in, e.g., Szoka, et al., U.S. Pat.Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporatedherein by reference.

The amount administered to the patient will vary depending upon what isbeing administered, the purpose of the administration, such asprophylaxis or therapy, the state of the patient, the manner ofadministration, and the like. In therapeutic applications, compositionsare administered to a patient already suffering from a disease in anamount sufficient to cure or at least partially arrest the symptoms ofthe disease and its complications. An amount adequate to accomplish thisis defined as “therapeutically effective dose.” Amounts effective forthis use will depend on the disease condition being treated as well asby the judgment of the attending clinician depending upon factors suchas the severity of the inflammation, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient are in the form ofpharmaceutical compositions described above. These compositions may besterilized by conventional sterilization techniques, or may be sterilefiltered. The resulting aqueous solutions may be packaged for use as is,or lyophilized, the lyophilized preparation being combined with asterile aqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention willvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. For example, for intravenous administration, the dose willtypically be in the range of about 20 μg to about 500 μg per kilogrambody weight, preferably about 100 μg to about 300 μg per kilogram bodyweight. Suitable dosage ranges for intranasal administration aregenerally about 0.1 pg to 1 mg per kilogram body weight. Effective dosescan be extrapolated from dose-response curves derived from in vitro oranimal model test systems.

Compounds of this invention are also capable of binding or antagonizingthe actions of α₆β₁, α₉β₁, α₄β₇, α_(d)β₂, α_(e)β₇ integrins (althoughα₄β₁ and α₉β₁ are preferred in this invention). Accordingly, compoundsof this invention are also useful for preventing or reversing thesymptoms, disorders or diseases induced by the binding of theseintegrins to their respective ligands.

For example, International Publication Number WO 98/53817, publishedDec. 3, 1998 (the disclosure of which is incorporated herein byreference in its entirety) and references cited therein describedisorders mediated by α₄β₇. This reference also describes an assay fordetermining antagonism of α₄β₇ dependent binding to VCAM-Ig fusionprotein.

Additionally, compounds that bind α_(d)β₂ and α_(e)β₇ integrins areparticularly useful for the treatment of asthma and related lungdiseases. See, for example, M. H. Grayson et al., J. Exp. Med. 1998,188(11) 2187-2191. Compounds that bind α_(e)β₇ integrin are also usefulfor the treatment of systemic lupus erythematosus (see, for example, M.Pang et al., Arthritis Rheum. 1998, 41(8), 1456-1463); Crohn's disease,ulcerative colitis and infammatory bowel disease (IBD) (see, forexample, D. Elewaut et al., Scand J. Gastroenterol 1998, 33(7) 743-748);Sjogren's syndrome (see, for example, U. Kroneld et al., Scand J.Gastroenterol 1998, 27(3), 215-218); and rheumatoid arthritis (see, forexample, Scand J. Gastroenterol 1996, 44(3), 293-298). And compoundsthat bind α₆β₁ may be useful in preventing fertilization (see, forexample, H. Chen et al., Chem. Biol. 1999, 6, 1-10).

Certain of the compounds within the generic formulas described hereinare also useful as synthetic intermediates for other compounds of thisinvention as illustrated in the examples herein.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

-   -   aq or aq.=aqueous    -   AcOH=acetic acid    -   bd=broad doublet.    -   bm=broad multiplet    -   bs=broad singlet    -   Bn=benzyl    -   Boc=N-tert-butoxylcarbonyl    -   Boc₂O=di-tert-butyl dicarbonate    -   BOP=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium        hexafluorophosphate    -   Cbz=carbobenzyloxy    -   CHCl₃=chloroform    -   CH₂Cl₂=dichloromethane    -   (COCl)₂=oxalyl chloride    -   d=doublet    -   dd=doublet of doublets    -   dt=doublet of triplets    -   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCC=1,3-dicyclohexylcarbodiimide    -   DMAP=4-N,N-dimethylaminopyridine    -   DME=ethylene glycol dimethyl ether    -   DMF=N,N-dimethylformamide    -   DMSO=dimethylsulfoxide    -   EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride    -   Et₃N=triethylamine    -   Et₂O=diethyl ether    -   EtOAc=ethyl acetate    -   EtOH=ethanol    -   eq or eq.=equivalent    -   Fmoc=N-(9-fluorenylmethoxycarbonyl)    -   FmocONSu=N-(9-fluorenylmethoxycarbonyl)-succinimide    -   g=grams    -   h=hour    -   H₂O=water    -   HBr=hydrobromic acid    -   HCl=hydrochloric acid    -   HOBT=1-hydroxybenzotriazole hydrate    -   hr=hour    -   K₂CO₃=potassium carbonate    -   L=liter    -   m=multiplet    -   MeOH=methanol    -   mg=milligram    -   MgSO₄=magnesium sulfate    -   mL=milliliter    -   mm=millimeter    -   mM=millimolar    -   mmol=millimol    -   mp=melting point    -   N=normal    -   NaCl=sodium chloride    -   Na₂CO₃=sodium carbonate    -   NaHCO₃=sodium bicarbonate    -   NaOEt=sodium ethoxide    -   NaOH=sodium hydroxide    -   NH₄Cl=ammonium chloride    -   NMM=N-methylmorpholine    -   Phe=L-phenylalanine    -   Pro=L-proline    -   psi=pounds per square inch    -   PtO₂=platinum oxide    -   q=quartet    -   quint.=quintet    -   rt=room temperature    -   s=singlet    -   sat=saturated    -   t=triplet    -   t-BuOH=tert-butanol    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC or tlc=thin layer chromatography    -   Ts=tosyl    -   TsCl=tosyl chloride    -   TsOH=tosylate    -   μL=microliter

The following Methods may be used to prepare the compounds of thisinvention.

Method A Methyl Ester Preparation Procedure

Amino acid methyl esters can be prepared using the method of Brenner andHuber. Hely. Chim. Acta 1953, 36, 1109.

Method B BOP Coupling Procedure

The desired dipeptide ester was prepared by the reaction of a carboxylicacid (1 equivalent) with the appropriate amino acid ester or amino acidester hydrochloride (1 equivalent),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate[BOP] (2.0 equivalent), triethylamine (1.1 equivalent), and DMF. Thereaction mixture was stirred at room temperature overnight. The crudeproduct is purified flash chromatography to afford the dipeptide ester.

Method C Hydrogenation Procedure I

Hydrogenation was performed using 10% palladium on carbon (10% byweight) in methanol at 30 psi overnight. The mixture was filteredthrough a pad of Celite and the filtrate concentrated to yield thedesired compound.

Method D Hydrolysis Procedure I

To a chilled (0° C.) THF/H₂O solution (2:1, 5-10 mL) of the appropriateester was added LiOH (or NaOH) (0.95 equivalents). The temperature wasmaintained at 0° C. and the reaction was complete in 1-3 hours. Thereaction mixture was extracted with ethyl acetate and the aqueous phasewas lyophilized resulting in the desired carboxylate salt.

Method E Ester Hydrolysis Procedure II

To a chilled (0° C.) THF/H₂O solution (2:1, 5-10 mL) of the appropriateester was added LiOH (1.1 equivalents). The temperature was maintainedat 0° C. and the reaction was complete in 1-3 hours. The reactionmixture was concentrated and the residue was taken up into H₂O and thepH adjusted to 2-3 with aqueous HCl. The product was extracted withethyl acetate and the combined organic phase was washed with brine,dried over MgSO₄, filtered and concentrated to yield the desired acid.

Method F Ester Hydrolysis Procedure III

The appropriate ester was dissolved in dioxane/H₂O (1:1) and 0.9equivalents of 0.5 N NaOH was added. The reaction was stirred for 3-16hours and then concentrated. The resulting residue was dissolved in H₂Oand extracted with ethyl acetate. The aqueous phase was lyophilized toyield the desired carboxylate sodium salt.

Method G BOC Removal Procedure

Anhydrous hydrochloride (HCl) gas was bubbled through a methanolicsolution of the appropriate Boc-amino acid ester at 0° C. for 15 minutesand the reaction mixture was stirred for three hours. The solution wasconcentrated to a syrup and dissolved in Et₂O and reconcentrated. Thisprocedure was repeated and the resulting solid was placed under highvacuum overnight.

Method H tert-Butyl Ester Hydrolysis Procedure I

The tert-butyl ester was dissolved in CH₂Cl₂ and treated with TFA. Thereaction was complete in 1-3 hr at which time the reaction mixture wasconcentrated and the residue dissolved in H₂O and lyophilized to yieldthe desired acid.

Method I EDC Coupling Procedure I

To a CH₂Cl₂ solution (5-20 mL) of a carboxylic acid (1 equivalent), theappropriate amino acid ester hydrochloride (1 equivalent), N-(1.1-2.2equivalents) and 1-hydroxybenzotriazole (2 equivalents) were mixed,placed in an ice bath and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide(1.1 equivalents) added. The reaction was allowed to rise to roomtemperature and stirred overnight. The reaction mixture was poured intoH₂O and the organic phase was washed with sat. NaHCO₃, brine, dried(MgSO₄ or Na₂SO₄), filtered and concentrated. The crude product waspurified by column chromatography.

Method J EDC Coupling Procedure II

To a DMF solution (5-20 mL) of a carboxylic acid (1 equivalent), theappropriated amino acid ester hydrochloride (1 equivalent); Et₃N (1.1equivalents) and 1-hydroxybenzotriazole (2 equivalents) were mixed,placed in an ice bath and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide(1.1 equivalents) added. The reaction was allowed to rise to roomtemperature and stirred overnight. The reaction mixture was partitionedbetween EtOAc and H₂O and the organic phase washed with 0.2 N citricacid, H₂O, sat. NaHCO₃, brine, dried (MgSO₄ or Na₂SO₄), filtered andconcentrated. The crude product was purified by column chromatography orpreparative TLC.

Method K tert-Butyl Ester Hydrolysis Procedure II

The tert-butyl ester was dissolved in CH₂Cl₂ (5 mL) and treated with TFA(5 mL). The reaction was complete in 1-3 hours at which time thereaction mixture was concentrated and the residue dissolved in H₂O andconcentrated. The residue was redissolved in H₂O and lyophilized toyield the desired product.

Method L Carbamate Formation Procedure I

Into a reaction vial were combined 15.2 mmol, 1.0 eq. of the startinghydroxy compound (typically a tyrosine derivative) and 1.86 g (15.2mmol, 1.0 eq) DMAP. Methylene chloride (50 mL), triethylamine (2.12 mL,1.54 g, 15.2 mmol, 1.0 eq), and dimethylcarbamyl chloride (1.68 mL, 1.96g, 18.2 mmol, 1.2 eq) were then added. The vial was capped tightly, andthe reaction solution swirled to obtain a homogeneous solution. Thereaction solution was then heated to 40° C. After 48 h, TLC of theresulting colorless solution indicated complete conversion. The work-upof the reaction solution was as follows: 50 mL EtOAc and 50 mL hexaneswas added to the reaction mixture, and the resulting mixture was washedwith 0.5 M citric acid (3×50 mL), water (2×50 mL), 10% K₂CO₃(2×50 mL),and sat. NaCl (1×50 mL); dried with MgSO₄, filtered and evaporated toafford the desired compound.

Method M Carbamate Formation Procedure II

Into a reaction vial were combined 84.34 mmol (1.0 eq) of the startinghydroxy compound (typically a tyrosine derivative) and 17.0 g (84.34mmol, 1.0 eq) 4-nitrophenyl chloroformate. Methylene chloride (700 mL)was added and the vial was capped with a septum. A nitrogen line wasattached and the vial was immersed in a 4:1 water/ethanol dry ice slurrywith stirring to cool to −15° C. Triethylamine (29.38 mL, 21.33 g,210.81 mmol, 2.5 eq) was added over five minutes with stirring and thestirring was continued at −10 to −15° C. for 1 h. N-Methyl piperazine(9.35 mL, 8.45 g, 84.34 mmol, 1.0 eq) was added over three minutes withstirring and stirring was continued overnight while warming to roomtemperature. The reaction mixture was diluted with 700 mL hexanes andthe resulting mixture was washed repeatedly with 10% K₂CO₃, until noyellow color (from 4-nitrophenol) is observed in the aqueous layer. Themixture was then washed with sat. NaCl, dried over anhydrous MgSO₄,filtered and evaporated. The residue was dissolved in 500 mL of ethanoland evaporated to remove triethylamine. The residue was again dissolvedin 500 mL of ethanol and evaporated to remove triethylamine. The residuewas then dissolved in 400 mL of ethanol and 600 mL of water was addedwith stirring to precipitate a solid or oil. If an oil if formed, theoil is stirred vigorously to induce it to solidify. The solid is thenisolated by filtration. Dissolution, precipitation, and filtration arerepeated once and the resulting solid is rinsed with water to removetraces of yellow color. The solid is then subjected to high vacuum untilthe mass remains constant thereby affording the desired carbamyloxycompound.

Method N Preparation of 5-Iodo-4(3H)-pyrimidinone

The procedure of Sakamoto et. al. (Chem. Pharm. Bull. 1986, 34(7),2719-2724) was used to convert 4(3H)-pyrimidinone into5-iodo-4(3H)-pyrimidinone, which was of sufficient purity for conversionto 4-chloro-5-iodopyrimidine.

Method O Preparation of 4-Chloro-5-iodopyrimidine

5-Iodo-4(3H)-pyrimidinone (1 eq.) was suspended in toluene to which wasadded POCl₃ (2.0 eq.). The reaction mixture was heated to reflux for 3hours, and then cooled and concentrated. The residue was suspended inwater, adjusted to pH=7 by addition of 4N sodium hydroxide, andextracted with ethyl acetate. The organic extracts were washed withbrine, dried (MgSO₄), filtered and stripped to give a red oil. The crudeproduct was dissolved in methanol and silica gel was added. Followingconcentration, the coated silica gel was loaded onto a plug of silicagel and elution with ethyl acetate/hexanes yielded the title compound.

Method P Preparation ofN-(5-Iodopyrimidine-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

A solution 4-chloro-5-iodopyrimidine (1.0 eq.),L-4-(N,N-dimethylcarbamyloxy)-phenylalanine tert-butyl ester (1.0 eq),and N,N-diisopropylethyl amine (2.0 eq) in tetrahydrofuran was heated atreflux for 16 hours. The reaction mixture was then cooled and dilutedwith water and ethyl acetate. The organic phase was washed with 0.2 Ncitric acid, water, saturated NaHCO₃, brine, dried (MgSO₄), filtered andconcentrated. The residue was purified by silica gel chromatographyusing ethyl acetate/hexanes to afford the title compound.

Method Q Suzuki Coupling Procedure I

To an ethyleneglycol dimethyl ether solution oftetrakis(triphenylphosphine)palladium (0.04 eq) was addedN-(5-iodopyrimidine-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (1.0 eq.). After stirring for approximately ten minutesa boronic acid or ester (1.2 eq) and 2M Na₂CO₃ (2.0 eq) were added, andthe reaction flask was evacuated and then flushed with nitrogen gas. Thereaction was heated at reflux from three to sixteen hours. The reactionmixture was then cooled, diluted with water and ethyl acetate, and theorganic phase was washed with 0.2 N citric acid, water, saturatedNaHCO₃, brine, dried (MgSO₄), filtered and concentrated. Alternatively,the cooled reaction mixture was diluted with ethyl acetate and washedwith water, saturated NaHCO₃, dried (MgSO₄), filtered and concentrated.Either column chromatography or preparative thin layer chromatography onsilica gel using ethyl acetate/hexanes afforded the desired product.

Method R Suzuki Coupling Procedure II

To a dimethylformamide solution oftetrakis(triphenylphosphine)-palladium (0.02-0.05 eq) was addedN-(5-iodopyrimidine-4-yl)-L-4-(N,N dimethylcarbamyloxy)phenylalaninetert-butyl ester (1.0 eq.). After stirring for approximately tenminutes, the boronic acid (1.1-4.0 eq) and K₃PO₄ (1.5-2.0 eq) wereadded, and the reaction was heated at 100° C. for three to sixteenhours. The reaction mixture was then cooled, diluted with water andethyl acetate, and the organic phase was washed with 0.2 N citric acid,water, saturated NaHCO₃, brine, dried (MgSO₄), filtered andconcentrated. Either column chromatography or preparative thin layerchromatography on silica gel using ethyl acetate/hexanes afforded thedesired product.

Method S Suzuki Coupling Procedure III

An ethyleneglycol dimethyl ether/2M Na₂CO₃ (1:1 by volume) solution oftetrakis(triphenylphosphine)palladium (0.04 eq),N-(5-iodopyrimidine-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (1.0 eq.), the boronic acid (1.1 eq) and lithiumchloride (3.0 eq) was heated to reflux for approximately six hours. Thecooled reaction mixture was diluted with ethyl acetate and washed withwater, brine, dried (MgSO₄), filtered and concentrated. The residue waspurified by silica gel column chromatography using ethyl acetate/hexanesto afford the desired product.

Method T Suzuki Coupling Procedure IV

An ethyleneglycol dimethyl ether/2M Na₂CO₃, (1:1 by volume) solution oftetrakis(triphenylphosphine)palladium (0.05 eq),N-(5-iodopyrimidine-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (1.0 eq.), the boronic acid (1.5 eq) andtri-o-tolylphosphine (0.1 eq) was heated to reflux for approximatelythree hours. The cooled reaction mixture was diluted with ethyl acetateand water and washed with water, brine, dried (MgSO₄), filtered andconcentrated. The residue was purified by preparative thin layerchromatography on silica gel using ethyl acetate/hexanes to afford thedesired product.

Method U Heck Reaction Procedure I

A dimethylformamide solution ofN-(5-iodopyrimidine-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (1.0 eq.), N,N-dimethylacrylamide (2.0 eq), andtriethylamine (6.0 eq) was degassed with nitrogen and thendichlorobis-(triphenylphosphine)palladium was added. The reaction waswarmed to 90° C. under a stream of nitrogen for 16 hours. The cooledreaction mixture was diluted with ethyl acetate and water and washedwith water, brine, dried (MgSO₄), filtered and concentrated. The residuewas purified by column chromatography on silica gel using ethylacetate/hexanes followed by preparative thin layer chromatography onsilica gel using ethyl acetate/hexanes to afford the desired product.

Method V Hydrogenation Procedure II

N-(5-(2-N,N-dimethylcarbamylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester was dissolved in ethanol to which was added 10%palladium on carbon. The reaction mixture was hydrogenated at 35 psihydrogen for approximately five hours. The reaction mixture was filteredthrough a pad of Celite, and the filtrate was concentrated. The residuewas purified by preparative thin layer chromatography on silica gelusing methanol/dichloromethane to afford the desired product.

Method W Heck Reaction Procedure II

To a tetrahydrofuran solution ofN-(5-iodopyrimidine-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (1.0 eq) dichlorobis(triphenylphosphine)palladium,triethylamine (0.05 eq) and triphenylphosphine (0.025 eq) was addedphenylacetylene (1.5 eq) and triethylamine (1.5 eq). After twentyminutes, copper (I) iodide (0.012 eq) was added, and the resultingmixture was stirred overnight at room temperature. The reaction mixturewas then diluted with ethyl acetate and water and washed with 0.2 Ncitric acid, water, saturated NaHCO₃, brine, dried (MgSO₄), filtered andconcentrated. The residue was chromatographed on a silica gel columnusing ethyl acetate/hexanes. ¹H NMR analysis showed that the desiredproduct to be contaminated with the iodopyrimidine starting material.However, the product was used without further purification.

Method X Hydrogenation Procedure III

CrudeN-(5-(2-phenylethynyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester was dissolved in ethanol to which was added 10%palladium on carbon and sodium acetate (3.0 eq). The reaction mixturewas hydrogenated at 40 psi hydrogen for approximately three hours, thenfiltered through a pad of Celite, and the filtrate concentrated. Theresidue was washed with 0.2 N citric acid, water, saturated NaHCO₃,brine, dried (MgSO₄), filtered and concentrated. Silica gel columnchromatography using ethyl acetate/hexanes yielded the desired product.

Method Y Preparation ofN-(6-Chloropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

A solution 4,6-dichloropyrimidine (1.2 eq),L-4-(N,N-dimethylcarbamyloxy)-phenylalanine tert-butyl ester (1.0 eq),and triethylamine (1.05 eq) in ethanol was heated at reflux for 16hours. The reaction mixture was cooled and concentrated, and the residuewas taken-up in water and ethyl acetate. The organic phase was washedwith 0.2 N citric acid, water, saturated NaHCO₃, brine, dried (MgSO₄),filtered and concentrated. The residue was purified by silica gelChromatography using ethyl acetate/hexanes to afford the title compound.

Method Z Suzuki Coupling Procedure V

An ethyleneglycol dimethyl ether solution oftetrakis(triphenylphosphine)palladium (0.12 eq),N-(6-chloropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetort-butyl ester (1.0 eq.) and triphenylphosphine (0.05 eq) was stirredfor approximately ten minutes. The boronic acid or ester (1.2-2.5 eq)and 2M Na₂CO₃ (2.0 eq) were added, and the reaction was heated at 90° C.for 16 to 72 hours. The reaction mixture was cooled and concentrated,and the residue was taken up in water and ethyl acetate. The organicphase was washed with 0.2 N citric acid, water, saturated NaHCO₃, brine,dried (MgSO₄), filtered and concentrated. The residue was purified bypreparative thin layer chromatography on silica gel using ethylacetate/hexanes to afford the desired product.

Method AA Preparation ofN-(6-(N-Alkylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

A mixture ofN-(6-chloropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (1.0 eq) and an alkylamine (10.0 eq) was heated in asealed tube at 120° C. for 16 hours. The reaction mixture was cooled anddiluted with ethyl acetate. The organic portion was washed with 0.2 Ncitric acid, water, saturated NaHCO₃, brine, dried (MgSO₄), filtered andconcentrated. The residue was purified by silica gel chromatographyusing ethyl acetate/hexanes to afford the desired compound.

Method BB Preparation of 4-N-Alkylamino-5-bromo-2-chloropyrimidine

A methanol solution of 5-bromo-2,4-dichloropyrimidine (1.0 eq), thealkylamine (1.05 eq, typicallyL-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester), andN,N-diisoproylethylamine (5.0 eq) was heated to 40° C. for 16 hours. Thereaction mixture was then concentrated, and the residue was taken up inethyl acetate. The organic portion was washed with 0.2 N citric acid,water, saturated NaHCO₃, brine, dried (MgSO₄), filtered andconcentrated. The crude material was purified by silica gelchromatography using ethyl acetate/hexanes to afford the desiredcompound.

Method CC Preparation of 4-N-Alkylamino-5-bromo-2-N-alkylaminopyrimidine

An isopropanol solution of the 4-N-alkylamino-5-bromo-2-chloropyrimidine(1.0 eq) and an alkylamine (5.0 eq) was heated in sealed tube at 130° C.for 3-5 hours. The reaction mixture was then cooled and washed with 0.2N citric acid, water, saturated NaHCO₃, brine, dried (MgSO₄), filteredand concentrated. The crude material was purified by silica gelchromatography using ethyl acetate/hexanes to afford the desiredcompound.

Method DD 4-N-Alkylamino-5-bromo-2-N-alkylaminopyrimidine SuzukiCoupling Procedure

To an ethyleneglycol dimethyl ether solution oftetrakis(triphenylphosphine)palladium (0.04 eq) was added an4-N-alkylamino-5-bromo-2-N-alkylaminopyrimidine (1.0 eq.). Afterstirring for approximately ten minutes, the boronic acid or ester (1.2eq) and 2M Na₂CO₃ (2.0 eq) was added, and the reaction flask wasevacuated and then flushed with nitrogen gas. The reaction was heated atreflux for three to four hours. The reaction mixture was then cooled anddiluted with water and ethyl acetate, and the organic phase was washedwith 0.2 N citric acid, water, saturated NaHCO₃, brine, dried (MgSO₄),filtered and concentrated. The residue was purified by either silica gelcolumn or preparative thin layer chromatography using ethylacetate/hexanes to afford the desired product.

Method EE Preparation of N-tert-Butoxycarbonyl-4-Iodo-L-phenyalanineMethyl Ester

The title compound was prepared from 4-iodo-L-phenylalanine by standardconditions described by Bodanszky and Bodanszky in The Practice ofPeptide Synthesis; Springer-Verlag: Berlin, 1984.

Method FF Preparation ofN-tert-Butoxycarbonyl-4-(2,6-dimethoxyphenyl)-L-phenyalanine MethylEster

To a dimethylformamide solution of tetrakis(triphenylphosphine)palladium(0.02-0.05 eq) was addedN-tert-butoxycarbonyl-4-(2,6-dimethoxyphenyl)-L-phenyalanine methylester (1.0 eq.). After stirring for approximately ten minutes,2,6-dimethoxyphenyl boronic acid (1.1 eq) and K₃PO₄ (2.0 eq) were added,and the reaction was heated at 100° C. for sixteen hours. The reactionmixture was then cooled, diluted with water and ethyl acetate, and theorganic phase was washed with 0.2 N citric acid, water, saturatedNaHCO₃, brine, dried (MgSO₄), filtered and concentrated. Columnchromatography on silica gel using ethyl acetate/hexanes afforded thedesired product.

Method GG Preparation of 4-(2,6-Dimethoxyphenyl)-L-phenyalanine MethylEster Trifluoroacetic Acid Salt

A methylene chloride solution ofN-tert-butoxycarbonyl-4-(2,6-dimethoxyphenyl)-L-phenyalanine methylester was treated with trifluoroacetic acid for six hours at roomtemperature. Concentration of the volatiles yielded the title compound.

Method HH tert-Butyl Ester Cleavage Procedure III

A methylene chloride solution of the appropriate tert-butyl ester wastreated with trifluoroacetic acid at room temperature. After 2-3 hoursthe volatiles were evaporated, and the residue was treated again withmethylene chloride and trifluoroacetic acid. After 2-3 hours thevolatiles were evaporated again to yield the desired compound.

Method II Preparation ofN-(5-Allylpyrimidin-4-yl)-L-4-(N,N-dimethyl-carbamyloxy)phenylalaninetert-Butyl Ester

N-(5-Iodo-pyrimidin-4-yl)-L-4-(N,N-dimethyl-carbamyloxy)phenylalaninetert-butyl ester (1.0 eq) was dissolved in dry DMF, withallyltributylstannane (1.1 eq), bis(triphenylphosphine)palladiumdichloride (0.03 eq) and LiCl (3.0 eq). The reaction mixture was flushedunder nitrogen, and heated to 90° C. for 2 hours. EtOAc was added, andthe organic layer was washed with water and brine, and dried over MgSO₄.After filtration and evaporation of the solvent under reduced pressure,the crude material was purified by column chromatography (silica gel)eluting with EtOAc/hexanes 1:3. The title material was isolated in goodyields.

Method JJ Preparation ofN-[5-propylpyrimidin-4-yl]-L-4-(N,N-dimethyl-carbamyloxy)phenylalaninetert-Butyl Ester

N-(5-Allylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester was dissolved in methanol and treated with a catalyticamount of 10% palladium on carbon. The mixture was shaken under 10 psihydrogen gas for 3 hours. Upon filtration though a pad of Celite, andevaporation of the solvent under reduced pressure, the desired materialwas isolated as a foam.

Method KK Preparation ofN-(5-propylpyrimidin-4-yl)-L-4-(N,N-dimethyl-carbamyloxy)phenylalanine

N-(5-Propylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester was treated with neat trifluoroacetic acid, and themixture was stirred for 5 h at room temperature. Upon evaporation of thesolvent under reduced pressure, the desired material was isolated as afoam.

Method LL Preparation of Dimethyl 2-Alkylmalonate

To a suspension of sodium hydride 60% dispersion in mineral oil (1.1 eq)in anhydrous THF was added slowly with stirring dimethyl malonate (1.1eq), causing the evolution of gas. To the resulting solution was added abromoalkane, iodoalkane, or trifluoromethanesulfonyloxyalkane (1.0 eq),and the mixture was heated to 50° C. for 48 h, at which point TLCindicated consumption of the bromoalkane, iodoalkane, ortrifluoromethanesulfonyloxyalkane. The mixture was diluted with diethylether and washed with 70% saturated sodium chloride. The organicextracts were treated with anhydrous magnesium sulfate, filtered, andevaporated to afford a dimethyl 2-alkylmalonate of sufficient purity forimmediate conversion to a 5-alkyl-4,6-dihydroxypyrimidine.

Method MM Preparation of Diethyl 2-Alkylidenylmalonate

Procedure B (p. 2759) of Houve and Winberg (J. Org. Chem. 1980, 45(14),2754-2763) was employed to react diethyl malonate with a ketone or analdehyde to afford a diethyl 2-alkylidenylmalonate of sufficient purityfor immediate conversion to a diethyl 2-alkylmalonate.

Method NN Preparation of Diethyl 2-Alkylmalonate

A diethyl 2-alkylidenylmalonate and an equal mass 10% palladium oncarbon were suspended in ethanol. The mixture was shaken under 55 psihydrogen gas for 24 h, at which point TLC indicated consumption of thediethyl 2-alkylidenylmalonate. The mixture was filtered through Celiteand evaporated to afford a diethyl 2-alkylmalonate of sufficient purityfor immediate conversion to a 5-alkyl-4,6-dihydroxypyrimidine.

Method OO Preparation of 5-Alkyl-4,6-dihydroxypyrimidine

To a diethyl 2-alkylmalonate or a dimethyl 2-alkylmalonate (1.0 eq) wasadded formamidine acetate (1.0 eq) and 25% sodium methoxide in methanol(3.3 eq). The resulting slurry was stirred vigorously and heated to 60°C. for 4 h, and then allowed to cool. The slurry was diluted with water,and acidified to pH=2 by addition of HCl. The resulting precipitate wascollected by filtration, washed with water, and dried under vacuum, toafford a 5-alkyl-4,6-dihydroxypyrimidine of sufficient purity forimmediate conversion to a 5-alkyl-4,6-dichloropyrimidine.

Method PP Preparation of 5-Alkoxy-4-hydroxypyrimidine

The method (p. 308) of Anderson et al. (Org. Proc. Res. Devel. 1997, 1,300-310) was employed to react a methyl alkoxyacetate, sodium methoxide,ethyl formate, and formamidine acetate to afford a5-alkoxy-4-hydroxypyrimidine of sufficient purity for immediateconversion to a 5-alkoxy-4-chloropyrimidine.

Method QQ Preparation of 5-Alkyl-4,6-dichloropyrimidine or5-Alkoxy-4-chloropyrimidine

To a 5-alkyl-4,6-dihydroxypyrimidine or a 5-alkoxy-4-hydroxypyrimidine(1.0 eq) were added phosphorus oxychloride (15.0 eq) andN,N-dimethylaniline (1.0 eq), and the mixture was heated to 100° C. for3 h, and then allowed to cool. The resulting solution was poured ontoice, and the mixture was extracted with dichloromethane. The organicextracts were treated with anhydrous magnesium sulfate, filtered, andevaporated to afford a 5-alkyl-4,6-dichloropyrimidine or a5-alkoxy-4-chloropyrimidine of sufficient purity for immediateconversion to a 5-alkyl-4-N-alkylamino-6-chloropyrimidine or a5-alkoxy-4-N-alkylaminopyrimidine.

Method RR Preparation of 5-Alkyl-4-N-alkylamino-6-chloropyrimidine or5-Alkoxy-4-N-alkylaminopyrimidine

To a solution of a 5-alkyl-4,6-dichloropyrimidine or a5-alkoxy-4-chloropyrimidine (1.0 eq) in ethanol were added an alkylamine (1.2 eq, typically L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester) and diisopropylethylamine (2.0 eq). The mixture wassealed in a pressure tube and heated to 120° C. for 48 h, at which pointTLC indicated consumption of the 5-alkyl-4,6-dichloropyrimidine or the5-alkoxy-4-chloropyrimidine. The mixture was evaporated, and the residuewas partitioned between ethyl acetate and pH=4.5 citrate buffer. Theorganic extracts were washed with saturated sodium chloride, treatedwith anhydrous magnesium sulfate, filtered, and evaporated. The residuewas purified by chromatography on silica gel using ethyl acetate andhexanes to afford a pure 5-alkyl-4-N-alkylamino-6-chloropyrimidine or5-alkoxy-4-N-alkylaminopyrimidine.

Method SS Preparation of 5-Alkyl-4-N-alkylaminopyrimidine (Procedure I)

A suspension of 5-alkyl-4-N-alkylamino-6-chloropyrimidine (1.0 eq), andan equal mass 10% palladium on carbon, and sodium bicarbonate (5.0 eq)in methanol was shaken under 55 psi hydrogen gas for 16 h, at whichpoint TLC indicated consumption of the5-alkyl-4-N-alkylamino-6-chloropyrimidine. The mixture was filteredthrough Celite and evaporated to give a residue, which was partitionedbetween ethyl acetate and 70% saturated sodium chloride. The organicextracts were treated with anhydrous magnesium sulfate, filtered, andevaporated. The residue was purified by chromatography on silica gelusing ethyl acetate and hexanes to afford a pure5-alkyl-4-N-alkylaminopyrimidine.

Method TT Preparation of 5-Alkyl-4-N-alkylaminopyrimidine (Procedure II)

A suspension of 5-alkyl-4-N-alkylamino-6-chloropyrimidine (1.0 eq),sodium acetate (10.0 eq), and zinc powder (20.0 eq) in a 9:1 mixture ofacetic acid and water was stirred vigorously at 40° C. for 72 h, atwhich point TLC indicated partial consumption of the5-alkyl-4-N-alkylamino-6-chloropyrimidine. The supernatant solution wasdecanted from remaining zinc and evaporated. The residue was partitionedbetween ethyl acetate and saturated sodium bicarbonate, and the organicextracts were treated with anhydrous magnesium sulfate, filtered, andevaporated. The residue was purified by chromatography on silica gelusing ethyl acetate and hexanes to afford a pure5-alkyl-4-N-alkylaminopyrimidine.

Method UU Preparation of N-Benzyloxycarbonyl-L-Tyrosine tert-Butyl Ester

To a 0° C. suspension of L-tyrosine tert-butyl ester (Bachem, 1.0 eq)and sodium bicarbonate (2.0 eq) in a 1:1 mixture of THF and water wasadded slowly with stirring benzyl chloroformate (1.1 eq). After theaddition, the mixture was stirred at 0° C. for 3 h and at roomtemperature for 24 h. The mixture was diluted with diethyl ether, andthe aqueous layer was separated. The organic extracts were washed withsaturated sodium chloride, treated with anhydrous magnesium sulfate,filtered, and evaporated to afford N-benzyloxycarbonyl-L-tyrosinetert-butyl ester of sufficient purity for immediate conversion of thetyrosine hydroxyl into a carbamate.

Method VV Preparation ofN-Benzyloxycarbonyl-L-4-(N,N-Dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

A mixture of N-benzyloxycarbonyl-L-tyrosine tert-butyl ester (1.0 eq),4-dimethylaminopyridine (1.0 eq), triethylamine (1.5 eq),dimethylcarbamylchloride (1.2 eq), and dichloromethane was heated to 37°C. for 16 h. The mixture was diluted with additional dichloromethane andwashed sequentially with 1.0 M potassium bisulfate, water, saturatedsodium bicarbonate, and saturated sodium chloride. The organic extractswere treated with anhydrous magnesium sulfate, filtered, and evaporatedto afford N-benzyloxycarbonyl-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester as a white solid of sufficient purity for immediateconversion to L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butylester.

Method WW Preparation of L-4-(N,N-Dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

A suspension of N-benzyloxycarbonyl-L-4-(N,N-tert-butyl ester and anequal mass of 10% palladium on carbon in methanol was shaken under 55psi hydrogen gas for 1 h, at which point TLC indicated consumption ofthe N-benzyloxy carbonyl-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester. The mixture was filtered through Celite and evaporatedto afford L-4-(N,N-dimethylcarbamyloxy)-phenylalanine tert-butyl esterof sufficient purity for immediate use in reactions withchloropyrimidines.

Method XX Preparation ofN-Benzyloxycarbonyl-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalaninetert-Butyl Ester

To a stirred solution maintained at 0° C. ofN-benzyloxycarbonyl-L-tyrosine tert-butyl ester (1.0 eq) andtriethylamine (2.5 eq) in dichloromethane was added 4-nitrophenylchloroformate (1.0 eq). The mixture was stirred for 30 min at 0° C., andthen 1-methylpiperazine (1.5 eq) was added, and then the mixture wasstirred for 2 h while warming to room temperature. The mixture wasdiluted with ethyl acetate and washed five times with 10% potassiumcarbonate and once with saturated sodium chloride. The organic extractswere treated with anhydrous magnesium sulfate, filtered, and evaporatedto affordN-benzyloxycarbonyl-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine,tert-butyl ester of sufficient purity for immediate conversion toL-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine tert-butyl ester.

Method YY Preparation ofL-4-(4-Methylpiperazin-1-ylcarbonyloxy)phenylalanine tert-Butyl Ester

A suspension ofN-benzyloxycarbonyl-L-4-(4-methylpiperazin-1-ylcarbonyloxy)-phenylalaninetert-butyl ester and an equal mass of 10% palladium on carbon inmethanol was shaken under 55 psi hydrogen gas for 1 h, at which pointTLC indicated consumption ofN-benzyloxycarbonyl-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalaninetert-butyl ester. The mixture was filtered through Celite and evaporatedto afford L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalaninetert-butyl ester of sufficient purity for immediate use in reactionswith chloropyrimidines.

Method ZZ tert-Butyl Ester Cleavage Procedure IV

The tert-butyl ester was dissolved in 96% formic acid and heated to 40°C. for 16 h, at which point TLC indicated consumption of the tert-butylester. The mixture was evaporated under a stream of air to give aresidue, which was stored under high vacuum for 72 h to afford the purecarboxylic acid.

Method AAA Preparation of 2,4-Dichloro-5-nitropyrimidine

5-Nitrouracil was treated with phosphorus oxychloride andN,N-dimethylaniline, according to the procedure of Whittaker (J. Chem.Soc. 1951, 1565), to give 2,4-dichloro-5-nitropyrimidine as an orangeoil, which was used without distillation immediately in the next step.

Method BBB Preparation ofN-(2-Chloro-5-nitropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

To a stirred solution of L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (6.38 g, 20.69 mmol) and N,N-diisopropylethylamine(5.40 mL, 4.01 g, 31.03 mmol) in 70 mL CH₂Cl₂ at 0° C., was added asolution of 2,4-dichloro-5-nitropyrimidine (3.25 g, 20.69 mmol) in 70 mLof CH₂Cl₂, at such a rate the temperature did not exceed 10° C. Afterthe addition, the mixture was stirred at 0-10° C. for 15 minutes, atwhich point TLC indicated conversion of 2,4-dichloro-5-nitropyrimidine.To the mixture were added 100 mL 1 M KHSO₄ and 200 mL diethyl ether. Theorganic layer was separated, washed (H₂O, sat. NaHCO₃, and sat. NaCl),dried (MgSO₄), filtered, and evaporated to giveN-(2-chloro-5-nitropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (9.52 g, 20.45 mmol, 99%) as an orange oil, which wasused immediately in the next step.

Method CCC Preparation ofN-(5-Aminopyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

A mixture ofN-(2-chloro-5-nitropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester (9.52 g, 20.45 mmol), Degussa-type 20% palladium oncarbon (9.5.2 g), NaHCO₃ (8.59 g, 102.2 mmol), and 165 mL MeOH wasshaken under 55 Psi H₂ for 16 h, at which point TLC indicated conversionofN-(2-chloro-5-nitropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester into a single product. The mixture was filtered throughCelite, and the filtrate was evaporated to give a residue, which wasdissolved by addition of 150 mL EtOAc and 75 mL H₂O. The organic layerwas separated, washed (sat. NaCl), dried (MgSO₄), filtered, andevaporated to giveN-(5-aminopyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (7.14 g, 17.79 mmol, 87%) as an orange solid, which wasused immediately in the next step.

Method DDD Preparation ofN-(5-(N-4-Toluenesulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

To a stirred solution ofN-(5-aminopyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester (1.00 g, 2.49 mmol) in 10 mL anhydrous pyridine at 0°C.; was added in portions 4-toluenesulfonylchloride (0.474 g, 2.49mmol). After the addition, the resulting red solution was stirred at 0°C. for 3 h, at which point TLC indicated nearly complete conversion ofN-(5-aminopyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester. To the mixture was added 3-dimethylaminopropylamine(0.325 mL, 0.264 g, 2.49 mmol), and the mixture was stirred for 30 minwhile warming to room temperature. The mixture was poured into 100 mL 1M KHSO₄, and extracted with 150 mL EtOAc. The organic layer was washed(2×1 M KHSO₄, H₂O, sat. NaHCO₃, sat. NaCl), dried (MgSO₄), filtered, andevaporated to give a brown residue, which was purified by flashchromatography using EtOAc/hexanes on silica gel, to giveN-(5-(N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (1.01 g, 1.81 mmol, 73%) as a clear oil.

Method EEE Preparation ofN-(5-(N-Methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

To a stirred two-phase mixture of 45 mL 1 M NaOH and 25 mL diethyl etherat 0° C., was added in portions 1-methyl-3-nitro-1-nitrosoguanidine(1.33 g, 9.05 mmol). After stirring for 25 min, at which point evolutionof N₂ had subsided, the bright yellow solution of diazomethane indiethyl ether was transferred by pipette to a stirred solution ofN-(5-(N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (1.01 g, 1.81 mmol) in 15 mL diethyl ether and 15 mLCH₂Cl₂ at 0° C. After stirring for 15 min, at which point TLC indicatedcomplete conversion ofN-(5-(N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester, excess AcOH was added to destroy unreacteddiazomethane. The mixture was diluted with 100 mL diethyl ether, washed(2×sat. NaHCO₃, sat. NaCl), dried (MgSO₄), filtered and evaporated togive a yellow residue, which was purified by flash chromatography usingEtOAc/hexanes on silica gel, to giveN-(5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (0.846 g, 1.48 mmol, 82%) as a clear oil.

Method FFF Preparation of Diethyl 2-(N,N-Dialkylamino)malonate

The appropriate amine (1.0 eq) was added to a 0° C. solution of diethylbromomalonate (1.0 eq) and N,N-diisopropylethyl amine (1.1 eq) inethanol. The mixture was stirred and allowed to warm room temperature.After 16 hours, the reaction mixture was concentrated and the residuewas suspended in ethyl acetate and sat. NaHCO₃. The organic portion waswashed with sat NaHCO₃, brine, dried (MgSO₄) filtered and concentratedto yield the diethyl 2-(N,N-dialkylamino)malonate, of sufficient purityfor immediate conversion to a5-(N,N-dialkylamino)-4,6-dihydroxypyrimidine

Method GGG Preparation of 5-(N,N-Dialkylamino)-4,6-dihydroxypyrimidine

A suspension of a diethyl 2-(N,N-dialkylamino)malonate (1.0 eq),formamidine acetate (1.10 eq.) and 25% sodium methoxide in methanol (3.3eq) was heated to 65° C. for 3.5 hours. The reaction mixture was cooledand diluted with water. The mixture was acidified to pH=4.5 by additionof dilute HCl. The resulting precipitate was collected by filtration,washed with water, and dried under vacuum to afford a5-(N,N-dialkylamino)-4,6-dihydroxypyrimidine of sufficient purity forimmediate conversion to a 5-(N,N-dialkylamino)-4,6-dichloropyrimidine.Alternatively, the acidified solution was evaporated to give a solidresidue, which was extracted with boiling ethanol. The ethanol extractswere filtered and concentrated to give a residue, which wasrecrystallized from isopropyl alcohol to afford a5-(N,N-dialkylamino)-4,6-dihydroxypyrimidine of sufficient purity forimmediate conversion to a 5-(N,N-dialkylamino)-4,6-dichloropyrimidine.

Method HHH Preparation of 5-(N,N-Dialkylamino)-4,6-dichloropyrimidine

A 5-(N,N-dialkylamino)-4,6-dihydroxypyrimidine (1.0 eq) was suspended inPOCl₃ (15.0 eq), and the mixture was heated to reflux for 16 hours. Thenthe mixture was cooled and carefully poured into a suspension of ethylether and aqueous K₂CO₃. The organic portion was washed with brine,dried (MgSO₄), filtered and concentrated to yield a5-(N,N-dialkylamino)-4,6-dichloro-pyrimidine of sufficient purity forimmediate reaction with alkylamines.

Method III Preparation of4-(N-Alkylamino)-5-(N,N-dialkylamino)-6-chloropyrimidine

A 5-(N,N-dialkylamino)-4,6-dichloropyrimidine (1.0 eq),L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester (1.5 eq) andN,N-diisopropyl ethylamine (1.5 eq) were dissolved in ethanol and heatedto 120° C. in a sealed tube for 72 h. The cooled reaction mixture wasconcentrated, and the residue dissolved in ethyl acetate. The ethylacetate solution was washed with 0.2 N citric acid, water, saturatedNaHCO₃, brine, dried (MgSO₄), filtered and concentrated. The residue waspurified by silica gel chromatography using ethyl acetate/hexanes toafford the 4-(N-alkylamino)-5-(N,N-dialkylamino)-6-chloropyrimidine.

Method JJJ Preparation of4-(N-Alkylamino)-5-(N,N-dialkylamino)pyrimidine

A 4-(N-Alkylamino)-5-(N,N-dialkylamino)-6-chloropyrimidine (1.0 eq), anequal mass of 10% palladium on carbon and NaHCO₃ (5.0 eq) were suspendedin methanol. The reaction mixture was hydrogenated at 45 psi hydrogenfor 16 hours and then filtered through a pad of Celite. The filtrate wasconcentrated, and the residue was dissolved in ethyl acetate. The ethylacetate solution was washed with water, brine, dried (MgSO₄), filteredand concentrated to yield an oil. The oil was purified by columnchromatorgraphy on silica gel using ethyl actate and hexanes to afford apure 4-(N-alkylamino)-5-(N,N-dialkylamino)pyrimidine.

Method KKK Suzuki Coupling Procedure V

To an ethyleneglycol dimethyl ether solution oftetrakis(triphenylphosphine) palladium (0.04 eq) was addedN-(5-bromo-2-chloro-pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (1:5 eq.). After stirring for approximately ten minuteso-tolylboronic acid (1.5 eq) and 2M Na₂CO₃ (2.0 eq) were added, and thereaction flask was evacuated and flushed with nitrogen gas. The reactionwas heated tp reflux for four hours. The reaction mixture was thencooled and diluted with water and methylene chloride. The organic phasewas separated and washed with brine, dried (MgSO₄), filtered andconcentrated. The residue was purified by silica gel chromatographyusing ethyl acetate/hexanes to afford the desired product.

Method LLL Preparation of L-Phenylalanine Isopropyl Ester Hydrochlorideor L-Tyrosine Isopropyl Ester Hydrochloride

Excess HCl gas was added with stirring to a suspension ofL-phenylalanine or L-tyrosine in excess isopropanol. The mixture washeated to reflux for 16 h, and then the volatiles were evaporated undervacuum to give L-phenylalanine isopropyl ester hydrochloride orL-tyrosine isopropyl ester hydrochloride of sufficient purity forimmediate use.

Method MMM Bromopyrimidine Debromination Procedure

The bromopyrimidine was dissolved in isopropyl alcohol to which wasadded 10% palladium on carbon. The reaction was hydrogenated at 45 psihydrogen. Filtration and concentration of the filtrate yielded thedesired dehalogenated pyrimidine.

Method NNN Preparation of 2-Isopropropoxypyrimidine

A 2-chloropyrimidine was dissolved in isopropyl alcohol to which wasadded diisopropylamine. The reaction was heated in a sealed tube for tendays at 130° C. The cooled reaction mixture was concentrated, and theproduct purified via silica gel column chromatography to yield the2-isopropoxypyrimidine.

Method OOO Heck Reaction Procedure III

To a dioxane/triethylamine (1:1 by volume) solution of theN-(5-iodopyridin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanineisopropyl ester (1.0 eq), triphenylphosphine (0.05 eq), copper (I)iodide (0.2 eq) was added phenylacetylene (4.0 eq). After flushing thesolution for ten minutes with nitrogen gas,dichlorobis(triphenylphosphine)palladium (0.10 eq) was added, and theresulting reaction mixture heated to 50° C. for 16 hours. The reactionmixture was then diluted with ethyl acetate and water, and the organicportion was washed with 0.2 N citric acid, water, saturated NaHCO₃,brine, dried (MgSO₄), filtered and concentrated. The residue waschromatographed on a silica gel column using ethyl acetate/hexanes toafford the desired product.

Method PPP Preparation ofN-[5-(Phenyl)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

N-[5-iodopyrimidine-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (123 mg, 0.2 mmol) was diluted in dry DMF (5 mL) undernitrogen with KOAc (3.0 eq, 73 mg), bis(pinacolato)diboron (1.1 eq, 63mg), and a catalytic amount of[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1). The reaction was heated for 2 hours at 100°C.: To this was added, K3PO4 (2.0 eq, 105 mg), iodobenzene (2.0 eq,0.056 mL) and an additional catalytic amount of[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1). The reaction mixture was stirred overnightat 100° C. EtOAc was added and the organic layer washed with brine,dried over MgSO4. Upon filtration, and evaporation of the solvent underreduced pressure, the crude material was eluted on column chromatography(silica gel) with EtOAc/hexanes 1:1. The desired material was isolatedin good yields.

Method QQQ Preparation of 2-Amino-3-Chloropyrazine

A mixture of 2,3-dichloropyrazine (Lancaster) and ammonium hydroxide washeated in a sealed tube at 100° C. for 24 h resulting in a whiteprecipitate. The precipitate was collected by filtration and dried undervacuum to afford 2-amino-3-chloropyrazine of sufficient purity forimmediate conversion to 2-chloro-3-nitropyrazine.

Method RRR Preparation of 2-Chloro-3-Nitropyrazine

The method (p. 1638) of Hartman et al. (J. Med. Chem. 1984, 27(12),1634-1639) was employed to convert 2-amino-3-chloropyrazine into2-chloro-3-nitropyrazine of sufficient purity for immediate use.

Method SSS Preparation of 4-Alkylamino-2-dialkylamino-5-nitropyrimidine

A solution of 1.0 eq 4-alkylamino-2-chloro-5-nitropyrimidine and 5.0 eqdialkylamine in THF was allowed to stand for 16 h. The mixture wasdiluted with ethyl acetate and then washed with pH=4.5 citrate bufferand saturated sodium chloride. The organic extracts were treated withanhydrous magnesium sulfate, filtered, and evaporated to give a residue,which was purified by chromatography on silica gel using ethyl acetate,and hexanes.

Method TTT Preparation of L-4-(2,6-Dimethoxyphenyl)phenylalanine MethylEster

To a stirred solution (DMF, 66 mL) of N-Boc-L-(p-iodo)phenylalaninemethyl ester (13.2 g, 32.7 mmol) prepared according to the procedure ofSchwabacher et al., J. Org. Chem. 1994, 59, 4206-4210) was addedPd(PPh₃)₄ (0.03 eq, 1.13 g, 1 mmol). The solution was stirred for 10 minand then 2,6-dimethoxyboronic acid (1.2 eq, 7.1 g, 39 mmol) and K₃PO₄(1.5 eq, 10.4 g, 49 mmol) were added. The reaction flask was evacuatedand flushed with nitrogen. This process was repeated twice and thereaction mixture was then heated to 100° C. under a stream of nitrogenfor about 3.5 h at which time TLC showed the reaction to be complete(4.5:1 hexanes:EtOAc, R_(f)=0.2, UV active). The reaction mixture wascooled and partitioned between water and ethyl acetate (200 mL each).The organic portion was washed with 0.2N citric acid (3×100 mL), brine(1×100 mL), dried (MgSO₄), filtered and stripped to a thick reddish oil,about 13 g. The resulting product was chromatographed on silica geleluting with 4.5:1 hexanes/EtOAc, R_(f)=0.2. The combined fractions werestripped and treated with methanol saturated with HCl to yield the titleintermediate as the hydrochloride salt.

Example 1 Synthesis ofN-(2-Chloro-5-nitropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanineStep A—Preparation of 2,4-Dichloro-5-nitropyrimidine

5-Nitrouracil (Aldrich Chemical Company) was treated with phosphorousoxychloride and N,N-dimethylaniline according to the procedure describedin Whittaker, J. Chem. Soc. 1951, 1565, to give2,4-dichloro-5-nitropyrimidine as an orange oil which was used withoutdistillation immediately in the next step.

Step B—Preparation ofN-(2-Chloro-5-nitropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

To a stirred solution of L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (6.38 g, 2069 mol) and N,N-diisopropylethylamine (5.40mL, 4.01 g, 31.03 mol.) in 70 mL CH₂Cl₂ at 0° C., was added a solutionof 2,4-dichloro-5-nitropyrimidine (3.25 g, 20.69 mol.) in 70 mL CH₂Cl₂at such a rate that the temperature did not exceed 10° C. After theaddition, the mixture was stirred at 0-10° C. for 15 minutes, at whichpoint TLC indicated conversion of the starting materials. To the mixturewere added 100 mL 1 M KHSO₄ and 200 mL diethyl ether. The organic layerwas separated, washed (H₂O, sat. NaHCO₃, and sat. NaCl), dried (MgSO₄),filtered, and evaporated to give the title compound (9.52 g, 2045 mol.,99%) as an orange oil.

Step C—Preparation ofN-(2-Chloro-5-nitropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

The title compound was prepared by hydrolysis of the product from Step Busing the procedure of Example 5.

Example 2 Synthesis ofN-[5-(N-4-Toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester Step A—Preparation ofN-(5-Aminopyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

A mixture ofN-(2-chloro-5-nitropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-butyl ester (9.52 g, 20.45 mol), Degussa-type 20% palladium oncarbon (9.52 g), NaHCO₃ (8.59 g, 102.2 mol), and 165 mL MeOH was shakenunder 55 psi for 16 h, at which point TLC indicated conversion of thestarting material into a single product. The mixture was filteredthrough Celite, and the filtrate was evaporated to give a residue, whichwas dissolved by addition of 150 mL EtOAc and 75 mL H₂O. The organiclayer was separated, washed (sat. NaCl), dried (MgSO₄), filtered, andevaporated to give the title intermediate (7.14 g, 17.79 mol, 87%) as anorange solid, which was used immediately in the next-step.

Step B—Preparation ofN-[5-(N-4-Toluenesulfonyl-amino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

To a stirred solution of the product from Step A (100 g, 2.49 mol) in 10ml., anhydrous pyridine at 0° C., was added in portions4-toluenesulfonyl chloride (0.474 g, 2.49 mol). After the addition, theresulting red solution was stirred at 0° C. for 3 h, at which point TLCindicated nearly complete conversion of the starting material. To themixture was added 3-dimethylaminopropylamine (0.325 mL, 0.264 g, 2.49mol), and the mixture was stirred for 30 min while warming to roomtemperature. The mixture was poured into 100 mL 1 M KHSO₄, and extractedwith 150 mL EtOAc. The organic layer was washed (2×1 M KHSO₄, H₂O, sat.NaHCO₃, sat. NaCl), dried (MgSO₄), filtered, and evaporated to give abrown residue, which was purified by flash chromatography usingEtOAc/hexanes on silica gel, to give the title compound (1.01 g, 1.81mol., 73%) as a clear oil.

Example 3 Synthesis ofN-[5-(N-4-Toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

The title compound was prepared by hydrolysis ofN-[5-(N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester using the procedure of Example 5.

Example 4 Synthesis ofN-[5-(N-Methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

To a stirred two-phase mixture of 45 mL 1 M NaOH and 25 mL diethyl etherat 0° C., was added in portions 1-methyl-3-nitro-1-nitrosoguanidine(1.33 g, 9.05 mol). After stirring for 25 min, at which point evolutionof N₂ had subsided, the bright yellow solution of diazomethane indiethyl ether was transferred by pipette to a stirred solution of theproduct of Example 2 (1.01 g, 1.81 mol) in 15 mL diethyl ether and 15 mLCH₂Cl₂ at 0° C. After stirring for 15 min, at which point TLC indicatedcomplete conversion of the starting material, excess AcOH was added todestroy unreacted diazomethane. The mixture was diluted with 100 mLdiethyl ether, washed (2×sat. NaHCO₃, sat. NaCl), dried (MgSO₄),filtered and evaporated to give a yellow residue, which was purified byflash chromatography using EtOAc/hexanes on silica gel, to give thetitle compound (0.846 g, 1.48 mol, 82%) as a clear oil.

Example 5 Synthesis ofN-[5-(N-Methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

The product of Example 4 (0.400 g, 0.700 mol) was dissolved in 8 mL 96%formic acid, and the mixture was heated to 40° C. for 16 h, at whichpoint TLC indicated conversion of the starting material. Most of theformic acid was evaporated under a stream of N₂, and then the residuewas placed under high vacuum for 48 h to give the title compound (0.382g, 0.700 mol, 100%) as a clear oil.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.33 (bs, 1H), 8.07 (bs, 1H), 7.64 (d, J=8.1 Hz, 2H),7.42 (d, J=8.1 Hz, 2H), 7.36 (bs, 1H), 7.29 (bs, 2H), 6.99 (d, J=7.5 Hz,2H), 5.07-4.96 (m, 1H), 3.42-3.31 (m, 1H), 3.25-3.15 (m, 1H), 3.08 (s,3H), 3.05 (bs, 3H), 2.96 (s, 3H), 2.44 (s, 3H).

¹³C NMR (CD₃OD): δ=174.7, 174.6, 164.6, 157.8, 156.8, 152.9, 152.1,146.5, 135.4, 135.1, 131.7, 131.3, 129.4, 123.2, 122.9, 55.8, 38.2,37.1, 36.8, 36.7, 21.5.

Using the appropriate starting materials and reagents, the followingadditional compounds were prepared:

-   N-[5-(N,N-Di-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    (Example 6);-   N-[5-[N-(1-N′-Methylpyrazol-4-ylsulfonyl)-N-methylamino]pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    (Example 7);-   N-[5-(N-Methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    isopropyl ester (Example 8);-   N-[5-(N-Methyl-N-3-pyridylsulfonylamino)pyrimidin-4-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    tert-butyl ester (Example 9); and

Example 10 Synthesis ofN-(5-(N-Methyl-N-(1-butylpyrazol-4-yl)sulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was, sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 5-Nitrouracil (Aldrich) was converted via Method AAAinto 2,4-dichloro-5-nitropyrimidine.L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butyl ester and2,4-dichloro-5-nitropyrimidine were coupled via Method BBB, and theproduct of this coupling was sequentially converted via Methods CCC, DDD(using 1-butyl-4-chlorosulfonylpyrazole), EEE and ZZ to give the titlecompound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.35 (s, 1H), 8.14 (s, 1H), 7.76 (s, 1H), 7.61 (bs,1H), 7.23 (bs, 2H), 6.98 (d, 2H), 5.01-4.94 (m, 1H), 4.19 (t, 2H),3.40-3.28 (m, 1H), 3.26-3.14 (m, 1H), 3.09 (s, 3H), 3.06 (bs, 3H), 2.96(s, 3H), 1.84 (pent., 2H), 1.29 (sext., 2H), 0.945 (t, 3H).

Example 11 Synthesis ofN-(5-(2,4-Dimethoxypyrimidin-5-yl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O into 4-chloro-5-iodopyrimidine.L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P, and the coupledproduct was reacted with 2,4-dimethoxypyrimidin-5-yl boronic acid(Frontier Scientific, Inc.) via Method S. The product of this couplingwas converted via Method KK to give the title compound.

Example 12

Synthesis ofN-(5-(2,6-Difluorophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O into 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P, and the coupledproduct was reacted with 2,6-difluorophenyl boronic acid (LancasterSynthesis) via Method R. The product of this coupling was converted viaMethod HH to give the title compound.

Example 13 Synthesis ofN-(5-(2-Hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O into 4-chloro-5-iodopyrimidine.L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P, and the coupledproduct was reacted with 2-(hydroxymethyl)phenyl boronic acid (LancasterSynthesis) via Method Q. The product of this coupling was converted viaMethod HH to give the title compound.

Example 14 Synthesis ofN-(2-(N-Cyclohexylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted with cyclohexylamine(Aldrich) via Method CC to give a product that was coupled with o-tolylboronic acid (Aldrich) via Method DD. The product of this coupling wasconverted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=9.68 (s, 1H), 7.3-6.8 (m, 9H), 6.35 (m, 1H), 4.73 (m,1H), 3.81 (bs, 1H), 3.6-3.0 (m, 2H), 3.09 (s, 3H), 3.0 (s, 3H), 2.18 (s,1.5H), 1.94 (s, 1.5H), 2.1-1.1 (m, 10H).

¹³C NMR (CDCl₃): δ=176.11, 175.94, 160.05, 159.79, 154.76, 153.58,150.05, 150.01, 139.26, 137.84, 137.63, 134.29, 134.15, 130.66, 130.36,130.11, 129.14, 126.70, 126.41, 121.25, 109.57, 109.39, 56.84, 56.35,50.15, 36.55, 36.32, 32.34, 31.99, 25.41, 24.86, 19.48, 19.27.

Example 15 Synthesis ofN-(2-(N-Methyl-N-(1-methylpiperidin-4-yl)amino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted with1-methyl-4-(N-methylamino)piperidine (Aldrich) via Method CC to give aproduct that was coupled with o-tolyl boronic acid (Aldrich) via MethodDD. The product of this coupling was converted via Method ZZ to give thetitle compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=8.82 (s, 2H), 8.43 (s, 1H), 7.62 (s, 1H), 7.30-6.90(m, 8H), 5.42 (br, 1H), 4.66 (br, 2H), 3.60-2.8 (m, 15H), 2.66 (bs, 3H),2.32 (br, 2H), 2.18 (s, 1.5H), 1.82 (brs, 3.5H).

Example 16 Synthesis ofN-(2-(N-Ethyl-N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-ethyl-N-isopropylamine (Aldrich) via Method CC to give a product thatwas coupled with o-tolyl boronic acid (Aldrich) via Method DD. Theproduct of this coupling was converted via Method ZZ to give the titlecompound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=8.0-6.5 (br, 1H), 7.66 (s, 0.5H), 7.62 (s, 0.5H),7.3-6.8 (m, 8H), 6.2 (m, 1H), 4.86 (br, 1H), 4.70 (m, 1H), 3.70-. 3.08(m, 4H), 3.09 (s, 3H), 3.0 (s, 3H), 2.14 (bs, 1.5H), 1.92 (bs, 1.5H),1.4-0.9 (br, 9H).

¹³C NMR (CDCl₃): δ=174.38, 174.19, 159.44, 159.16, 155.24, 154.68,152.39, 150.02, 141.63, 137.77, 137.56, 134.30, 134.09, 130.79, 130.66,130.54, 130.46, 130.41, 130.33, 130.08, 129.07, 126.54, 126.45, 126.38,121.21, 121.16, 110.27, 110.01, 56.77, 56.36, 47.59, 36.80, 36.55,36.32, 20.27, 20.18, 19.57, 19.38, 14.51.

Example 17 Synthesis ofN-(5-(2,4-6-Trimethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O into 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P, and the coupledproduct was reacted with 2,4,6-trimethylphenyl boronic acid (FrontierScientific, Inc) via Method R. The product of this coupling wasconverted via Method HH to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.68 (d, 1H), 7.95 (d, 1H), 7.10 (d, 2H), 7.09-6.95(m, 2H), 6.94-6.91 (m, 2H), 5.32-5.27 (m, 1H), 3.42-3.36 (m, 1H),3.15-3.09 (m, 4H), 2.97 (s, 3H), 2.33 (s, 3H), 2.04 (s, 3H), 1.84 (s,3H).

¹³C NMR (CD₃OD): δ=172.9, 163.5, 161.5, 161.0, 156.7, 152.0, 151.9,142.6, 141.5, 138.9, 138.6, 135.3, 131.2, 130.4, 130.3, 126.5, 123.0,120.3, 56.4, 36.7, 36.6, 36.5, 21.2, 19.9, 19.7.

Example 18 Synthesis ofN-(5-Isopropylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. Diethyl 2-isopropylmalonate (Aldrich) was sequentiallyconverted via Methods OO and QQ into 4,6-dichloro-5-isopropylpyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4,6-dichloro-5-isopropylpyrimidine were coupled via Method RR, and theproduct of this coupling was sequentially converted via Methods SS andZZ to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.44 (bs, 1H), 7.94 (bs, 1H), 7.22 (d, 2H), 6.94 (d,2H), 5.12 (dd, 1H), 3.46 (dd, 1H), 3.19 (dd, 1H), 3.07 (s, 3H), 2.95 (s,3H), 3.00-2.88 (m, 1H), 1.25 (d, 3H), 1.13 (d, 3H).

¹³C NMR (CD₃OD): δ=175.60, 165.74, 163.78, 156.91, 152.38, 151.85,141.88, 136.30, 131.43, 126.17, 122.87, 57.84, 37.48, 36.81, 36.64,26.63, 21.09, 20.94.

Example 19 Synthesis ofN-(2-(N-Methyl-N-butylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methyl-N-butylamine (Aldrich) via Method CC to give a product that wascoupled with o-tolyl boronic acid (Aldrich) via Method DD. The productof this coupling was converted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=12.5-11.4 (br, 1H), 7.6 (s, 0.5H), 7.58 (s, 0.5H),7.3-6.8 (m, 8H), 6.3 (m, 1H), 4.7 (m, 1H), 3.7-2.9 (m, 4H), 3.08 (s,3H), 3.01 (s, 6H), 2.13 (s, 1.5H), 1.91 (s, 1.5H), 1.57 (bs, 2H), 1.33(m, 2H), 0.96 (t, 3H).

¹³C NMR (CDCl₃): δ=174.21, 174.06, 159.37, 159.22, 154.69, 153.52,169.99, 141.87, 137.77, 137.54, 134.43, 130.78, 130.59, 130.10, 128.98,126.51, 126.32, 121.17, 121.11, 110.20, 109.96, 56.82, 56.43, 50.03,36.54, 36.32, 35.91, 29.27, 19.89, 19.52, 19.35, 13.84.

Example 20 Synthesis ofN-(2-(N-Ethyl-N-propylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-ethyl-N-propylamine (Aldrich) via Method CC to give a product that wascoupled with o-tolyl boronic acid (Aldrich) via Method DD. The productof this coupling was converted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=11.0-9.5 (br, 1H), 7.66 (s, 0.5H), 7.64 (s, 0.5H),7.4-6.8 (m, 8H), 6.28 (m, 1H), 4.65 (m, 1H), 3.70-2.80 (m, 6H), 3.09 (s,3H), 3.01 (s, 3H), 3.01 (s, 3H), 2.2 (s, 1.5H), 1.85 (s, 1.5H), 1.58(bs, 2H), 1.05 (bs, 3H), 0.85 (bs, 3H).

¹³C NMR (CDCl₃): δ=174.26, 174.11, 159.36, 159.11, 154.70, 153.07,149.96, 142.43, 137.80, 137.56, 134.54, 134.37, 130.84, 130.74, 130.57,130.14, 128.86, 126.47, 126.29, 121.10, 121.06, 110.01, 109.71, 56.86,56.49, 49.62, 63.20, 36.55, 36.32, 20.87, 19.61, 19.41, 12.63, 11.03.

Example 21 Synthesis ofN-(2-(N,N-Diethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN,N-diethylamine (Aldrich) via Method CC to give a product that wascoupled with o-tolyl boronic acid (Aldrich) via Method DD. The productof this coupling was converted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=12.2 (br, 1H), 7.63 (s, 0.5H), 7.60 (s, 0.5H),7.40-6.80 (m, 8H), 6.28 (m, 1H), 4.70 (m, 1H), 3.80-2.90 (m, 6H), 3.06(s, 3H), 2.98 (s, 3H), 2.13 (s, 1.5H), 1.92 (s, 1.5H), 0.90 (s, 6H).

¹³C NMR (CDCl₃): δ=174.34, 174.15, 159.4, 159.1, 154.70, 152.66, 169.97,142.06, 137.76, 137.55, 134.44, 134.27, 130.81, 130.57, 130.10, 128.95,126.48, 126.32, 121.14, 121.08, 110.08, 109.80, 56.78, 56.37, 42.77,36.53, 36.31, 19.57, 19.38, 12.77.

Example 22 Synthesis ofN-(2-(N-Methyl-N-ethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted-via.Methods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methyl-N-ethylamine (Aldrich) via Method CC to give a product that wascoupled with o-tolyl boronic acid (Aldrich) via Method DD. The productof this coupling was converted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=12.5 (br, 2H), 8.23 (s, 1H), 7.50 (s, 0.5H), 7.44 (s,0.5H), 7.30-6.80 (m, 8H), 6.10 (m, 1H), 4.75 (m, 1H), 3.58 (bs, 2H),3.30 (m, 1H), 3.00 (m, 1H), 3.08 (s, 3H), 3.00 (s, 3H), 2.93 (s, 3H),2.08 (s, 1.5H), 1.92 (s, 1.5H), 1.50 (s, 3H).

¹³C NMR (CDCl₃): δ=174.63, 174.34, 165.72, 159.96, 159.72, 154.88,152.62, 150.49, 150.45, 140.64, 137.90, 137.81, 133:83, 133.65, 131.03,130.95, 130.85, 130.63, 130.10, 130.04, 129.76, 129.62, 126.88, 126.72,121.70, 121.61, 110.69, 110.46, 56.65, 56.11, 45.16, 36.57, 36.35,35.17, 19.38, 19.17, 11.96.

No Example 23 Example 24 Synthesis ofN-(5-Benzyloxypyrimidin-4-yl)-L-phenylalanine

Methyl 2-benzyloxyacetate (Aldrich) was sequentially converted viaMethods PP and QQ into 4-chloro-5-benzyloxypyrimidine. L-4-phenylalaninetert-butyl ester (Bachem) and 4-chloro-5-benzyloxypyrimidine werecoupled via Method RR, and the product of this coupling was convertedvia Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.54 (s, formate), 8.03 (s, 1H), 7.67 (s, 1H),7.37-7.31 (m, 5H), 7.17-7.12 (m, 5H), 5.11 (s, 2H), 4.78-4.75 (m, 1H),3.35-3.11 (m, 2H).

¹³C NMR (CD₃OD): δ=159.07, 143.16, 132.35, 130.64, 124.52, 123.94,123.83, 123.59, 123.11, 122.00, 99.47, 66.28, 50.32, 32.05.

Example 25 Synthesis ofN-(5-Benzyloxypyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. Methyl 2-benzyloxyacetate (Aldrich) was sequentiallyconverted via Methods PP and QQ into 4-chloro-5-benzyloxypyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-benzyloxypyrimidine were coupled via Method RR, and theproduct of this coupling was converted via Method ZZ to give the titlecompound.

Example 26 Synthesis ofN-(5-(N-Methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-phenylalanine

5-Nitrouracil (Aldrich) was converted via Method AAA into2,4-dichloro-5-nitropyrimidine. L-4-Phenylalanine tert-butyl ester(Bachem) and 2,4-dichloro-5-nitropyrimidine were coupled via Method BBB,and the product of this coupling was sequentially converted via MethodsCCC, DDD, EEE and ZZ to give the title compound.

Example 27 Synthesis ofN-(5-(N-Methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 5-Nitrouracil (Aldrich) was converted via Method AAAinto 2,4-dichloro-5-nitropyrimidine.L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butyl ester and2,4-dichloro-5-nitropyrimidine were coupled via Method BBB, and theproduct of this coupling was sequentially converted via Methods CCC, DDD(using 3-chlorosulfonylpyridine), EEE and ZZ to give the title compound.

Physical data were as follows:

¹NMR (CD₃OD): δ=8.90 (d, 1H), 8.85 (d, 1H), 8.36 (s, 1H), 8.15 (d, 1H),7.64 (dd, 1H), 7.53 (bs, 1H), 7.27 (bs, 2H), 6.99 (d, 2H), 5.04-4.87 (m,1H), 3.40-3.28 (m, 1H), 3.26-3.16 (m, 1H), 3.13 (bs, 3H), 3.09 (s, 3H),2.97 (s, 3H).

Example 28 Synthesis ofN-(5-Phenylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O to 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P, and the coupledproduct was reacted with phenyl boronic acid (Aldrich) via Method S. Theproduct of this coupling was converted via Method HH to give the titlecompound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.62 (s, 1H), 8.04 (s, 1H), 7.53-7.51 (m, 3H),7.30-7.27 (m, 2H), 7.17-7.15 (m, 2H), 7.00-6.97 (m, 2H), 5.27-5.22 (m,1H), 3.45-3.39 (m, 1H), 3.16-3.08 (m, 4H), 2.96 (s, 3H).

¹³C NMR (CD₃OD): δ=173.8, 163.7, 157.5, 152.8, 152.3, 142.4, 135.9,132.2, 132.1, 131.8, 130.7, 123.9, 122.4, 57.7, 37.7, 37.5.

Example 29 Synthesis ofN-(3-(N-Methyl-N-4-toluenesulfonylamino)pyrazin-2-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 2,3-Dichloropyrazine (Lancaster) was converted viaMethod QQQ and RRR into 2-chloro-3-nitropyrazine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and2-chloro-3-nitropyrazine were coupled via Method BBB, and the product ofthis coupling was sequentially converted via Methods CCC, DDD, EEE andZZ to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.07 (s, formate), 7.94 (d, 1H), 7.59 (d, 2H), 7.51(d, 1H), 7.36 (d, 2H), 7.29 (d, 2H), 7.01 (d, 2H), 4.90 (m, 1H),3.30-3.18 (m, 2H), 3.08 (s, 3H), 2.96 (s, 3H), 2.94 (s, 3H), 2.43 (s,3H).

¹³C NMR (CD₃OD): δ=177.07, 169.41, 158.64, 150.92, 147.23, 145.92,139.97, 137.14, 133.12, 129.62, 128.90, 125.69, 124.67, 124.08, 116.86,49.99, 31.67, 31.28, 30.77, 30.62, 15.46.

No Example 30 Example 31 Synthesis ofN-(5-(2,2,2-Trifluoroethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 1-Trifluoromethanesulfonyloxy-2,2,2-trifluoroethanewas sequentially converted via Methods LL, OO and QQ into4,6-dichloro-5-(2,2,2-trifluoroethyl)pyrimidine.L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butyl ester and4,6-dichloro-5-(2,2,2-trifluoroethyl)pyrimidine were coupled via MethodRR, and the product of this coupling was sequentially converted viaMethods SS and ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.41 (s, 1H), 8.09 (s, formate), 8.06 (s, 1H), 7.24(d, 2H), 6.96 (d, 2H), 5.06 (m, 1H), 3.60-3.40 (m, 2H), 3.37-3.11 (m,2H), 3.08 (s, 3H), 2.96 (s, 3H).

¹³C NMR (CD₃OD): δ=169.35, 158.91, 156.43, 151.33, 150.97, 148.87,145.76, 130.21, 125.27, 116.80, 50.80, 31.34, 30.75, 30.60, 26.65,26.23.

Example 32 Synthesis ofN-(5-(N-Methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanineIsopropyl. Ester

L-Tyrosine (Aldrich) was sequentially converted via Methods LLL, UU, XXand YY into L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanineisopropyl ester. 5-Nitrouracil (Aldrich) was converted via Method AAAinto 2,4-dichloro-5-nitropyrimidine.L-4-(4-Methylpiperazin-1-ylcarbonyloxy)phenylalanine isopropyl ester and2,4-dichloro-5-nitropyrimidine were coupled via Method BBB, and theproduct of this coupling was sequentially converted via Methods CCC, DDD(using 3-chlorosulfonylpyridine) and EEE to give the title compound.

Example 33 Synthesis ofN-(5-Benzylpyrimidine-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. Diethyl 2-benzylmalonate (Aldrich) was sequentiallyconverted via Methods OO and QQ into 4,6-dichloro-5-benzylpyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4,6-dichloro-5-benzylpyrimidine were coupled via Method RR, and theproduct of this coupling was sequentially converted via Methods SS andZZ to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.41 (s, 1H), 8.13 (s, formate), 7.80 (s, 1H)7.34-7.19 (m, 3H), 7.17 (d, 2H), 7.00 (d, 2H), 6.85 (d, 2H), 5.01 (m,1H), 3.82 (m, 2H), 3.09 (s, 3H), 3.09-2.97 (m, 2H), 2.97 (s, 3H).

¹³C NMR (CD₃OD): δ=159.31, 156.23, 150.88, 148.07, 145.70, 141.38,131.56, 129.81, 125.30, 124.21, 124.01, 122.37, 116.81, 51.35, 31.68,30.78, 30.61, 28.28.

Example 34 Synthesis ofN-(5-(N-Methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalaninetert-Butyl Ester

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, XX and YY intoL-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine tert-butyl ester.5-Nitrouracil (Aldrich) was converted via Method AAA into2,4-dichloro-5-nitropyrimidine.L-4-(4-Methylpiperazin-1-ylcarbonyloxy)phenylalanine tert-butyl esterand 2,4-dichloro-5-nitropyrimidine were coupled via Method BBB, and theproduct of this coupling was sequentially converted via Methods CCC, DDD(using 3-chlorosulfonylpyridine) and EEE to give the title compound.

Example 35 Synthesis ofN-(5-(2-Trifluoromethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted via UU,VV and WW into L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butylester. 4(3H)-Pyrimidinone (Aldrich) was sequentially converted viaMethods N and O to 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P and the coupledproduct was reacted with 2-trifluoromethylphenyl boronic acid (Aldrich)via Method Q. The product of this coupling was converted via Method HHto give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.51 (s, 1H), 7.84-7.49 (m, 2H), 7.71-7.63 (m, 2H),7.37 (d, 1H), 7.11-6.97 (m, 4H), 6.88 (d, 1H), 4.99 (s, 1H), 3.37-3.19(m, 1H), 3.14-3.02 (m, 4H), 2.97 (s, 3H).

¹³C NMR (CD₃OD): δ=175.7, 175.5, 165.6, 161.9, 161.7, 158.6, 157.6,157.5, 153.3, 153.1, 152.6, 152.5, 136.4, 136.2, 135.0, 134.9, 134.5,133.1, 132.2, 131.9, 131.7, 128.9, 128.7, 127.8, 124.3, 123.6.

No Example 36 Example 37 Synthesis ofN-(5-(2-N,N-Dimethylcarbamylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O to 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P and the coupledproduct was reacted with dimethylacrylamide (Aldrich) via Method U. Theproduct of this reaction which was sequentially converted via Methods Vand HH to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.56 (s, 1H), 8.06 (s, 1H), 7.32 (d, 2H), 7.01 (d,2H), 5.35-5.30 (m, 1H), 3.56-3.49 (m, 1H), 3.23-3.18 (m, 1H), 3.11 (s,3H), 3.02 (s, 3H), 2.99 (s, 3H), 2.97 (s, 3H), 2.88 (t, 2H), 2.65 (t,2H).

¹³C NMR (CD₃OD): δ=174.5, 174.2, 152.7, 151.6, 142.6, 136.5, 132.0,123.8, 121.0, 57.8, 38.4, 37.9, 37.5, 36.9, 32.2, 24.6.

Example 38 Synthesis ofN-(5-(N-Methyl-N-3-(1-methylpyrazole)sulfonylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanineIsopropyl Ester

L-Tyrosine (Aldrich) was sequentially converted via Methods LLL, UU, VVand WW into L-4-(N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester.5-Nitrouracil (Aldrich) was converted via Method AAA into2,4-dichloro-5-nitropyrimidine.L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine isopropyl ester and2,4-dichloro-5-nitropyrimidine were coupled via Method BBB, and theproduct of this coupling was sequentially converted via Methods CCC, DDD(using 1-methyl-3-chlorosulfonylpyrazole) and EEE to give the titlecompound.

Physical data were as follows:

¹H NMR (CDCl₃) δ=8.47 (s, 1H), 7.76 (s, 1H), 7.68 (bs, 2H), 7.19 (m,2H), 7.04 (d, 2H), 6.17 (d, 1H), 5.03 (m, 2H), 3.95 (s, 3H), 3.31-3.12(m, 2H), 3.08 (s, 3H), 3.06 (s, 3H), 2.99 (s, 3H), 1.24 (d, 3H), 1.21(d, 3H).

Example 39 Synthesis ofN-(6-Phenylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 4,6-dichloropyrimidine (Aldrich) were coupled via Method Y andthe coupled product was reacted with phenyl boronic acid (Aldrich) viaMethod Z. The product of this coupling was converted via Method HH togive the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.65 (s, 1H), 7.82-7.79 (m, 2H), 7.77-7.62 (m, 3H),7.31 (d, 2H), 7.06-7.01 (m, 4H), 5.32-5.28 (m, 1H); 3.50-3.44 (m, 1H),3.20-3.06 (m, 4H), 2.99 (s, 3H).

¹³C NMR (CD₃OD): δ=173.9, 165.7, 157.6, 154.9, 154.3, 152.8, 135.8,134.6, 132.3, 132.2, 131.7, 129.2, 123.8, 104.6, 57.8, 38.8, 37.7, 37.5.

Example 40 Synthesis ofN-(6-(2-Trifluoromethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 4,6-dichloropyrimidine (Aldrich) were coupled via Method Y andthe coupled product was reacted with 2-trifluoromethylphenyl boronicacid (Aldrich) via Method Z. The product of this coupling was convertedvia Method HH to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.46 (s, 1H), 7.95-7.82 (m, 1H), 7.73-7.67 (m, 2H),7.50-7.48 (m, 1H), 7.29 (d, 2H), 7.03 (d, 2H), 6.65 (s, 1H), 5.05 (s,1H), 3.39 (m, 1H), 3.16-3.12 (m, 4H), 3.00 (s, 3H).

¹³C NMR (CD₃OD): δ=176.0, 164.3, 158.8, 157.7, 152.6, 136.6, 139.0,132.9, 132.1, 131.4, 130.1, 129.7, 128.2, 128.2, 123.6, 38.8, 37.7,37.5.

Example 41 Synthesis ofN-(6-(2-Hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 4,6-dichloropyrimidine (Aldrich) were coupled via Method Y andthe coupled product was reacted with 2-(hydroxymethyl)phenyl boronicacid, (Lancaster Synthesis) via. Method Z. The product of this couplingwas converted-via Method HH to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.48 (s, 1H), 8.09 (s, 1H), 7.61-7.44 (m, 4H), 7.29(d, 2H), 7.02 (d, 2H), 6.71 (s, 1H), 5.27 (s, 2H), 5.10-5.02 (m, 1H),3.42-3.41 (m, 1H), 3.16-3.12 (m, 4H), 2.99 (s, 3H).

¹³C NMR (CD₃OD): δ=175.7, 165.6, 164.7, 158.0, 157.6, 152.6, 141.6,138.5, 136.7, 135.8, 132.2, 131.9, 131.7, 131.4, 131.3, 123.7, 64.9,64.3, 38.9, 37.7, 37.5.

Example 42 Synthesis ofN-(5-Cyclohexylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. Cyclohexanone (Aldrich) was sequentially converted viaMethods MM, NN, OO and QQ into 4,6-dichloro-5-cyclohexylpyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4,6-dichloro-5-cyclohexylpyrimidine were coupled via Method RR, and theproduct of this coupling was sequentially converted via Methods SS andZZ to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.41 (bs, 1H), 7.89 (bs, 1H), 7.21 (d, 2H), 6.94 (d,2H), 5.12 (dd, 1H), 3.47 (dd, 1H), 3.19 (dd, 1H), 3.06 (s, 3H), 2.95 (s,3H), 3.0 (m, 1H), 2.88-2.57 (bs, 1H), 2.5 (bs, 1H), 1.95-1.67 (m, 1H).

¹³C NMR (CD₃OD): δ=175.68, 165.82, 156.87, 152.10, 151.88, 141.96,136.30, 131.44, 125.38, 122.89, 57.86, 37.44, 36.81, 36.64, 36.30,32.65, 32.13, 27.29, 27.25, 26.95.

Example 43 Synthesis ofN-(2-(N-Methyl-N-2-furanmethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methylfurfurylamine (Salor) via Method CC to give a product that wascoupled with o-tolyl boronic acid (Aldrich) via Method DD. The productof this coupling was converted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=7.43-7.35 (m, 2H), 7.35-7.2 (m, 2H), 7.2-7.0 (m, 4H),7.0-6.9 (m, 2H), 6.42 (d, 1H), 6.39 (d, 1H), 4.85 (m, 1H), 3.3-3.1 (m,7H), 3.09 (s, 3H), 2.98 (s, 3H), 2.16 (s, 3H), 1.89 (s, 3H).

Example 44 Synthesis ofN-(2-(N-Methyl-N-4-chlorophenylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methyl-4-chloroaniline (Aldrich) via Method CC to give a product thatwas coupled with o-tolyl boronic acid (Aldrich) via Method DD. Theproduct of this coupling was converted via Method ZZ to give the titlecompound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.17 (s, 1H), 7.56-7.34 (m, 8H), 7.1-6.97 (m, 4H),3.50 (m, 2H), 3.13 (s, 3H), 2.1 (s, 3H), 2.17 (s, 3H), 1.94 (s, 3H).

Example 45 Synthesis ofN-(5-(3-Thienyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O into 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P and the coupledproduct was reacted with 3-thiophenyl boronic acid (Frontier Scientific,Inc.) via Method S. The product of this coupling was converted viaMethod KK to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.62 (s, 1H), 8.13 (s, 1H), 7.62 (m, 1H), 7.59 (m,1H), 7.20 (d, 2H), 7.09 (d, 1H), 7.01 (d, 2H), 3.47-3.13 (m, 2H), 3.13(s, 3H), 2.97 (s, 3H).

¹³C NMR: δ=173.22, 162.83, 156.84, 152.17, 151.43, 141.46, 135.22,131.54, 131.35, 129.96, 127.99, 127.90, 123.24, 117.13, 56.87, 36.82,36.64.

Example 46 Synthesis ofN-(5-(2-Thienyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O to 4-chloro-5-iodopyrimidine.L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P, and the coupledproduct was reacted with 2-thiophenyl boronic acid (Frontier Scientific,Inc.) via Method S. The product of this coupling was converted viaMethod KK to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.10 (s, 1H), 7.67 (s, 1H), 7.19 (d, 1H), 6.73 (m,4H), 6.49 (m, 2H), 4.80 (m, 1H), 2.89 (m, 1H), 2.70 (m, 1H), 2.60 (s,3H), 2.45 (s, 3H).

¹³C NMR (CD₃OD): δ=173.07, 162.72, 156.80, 152.13, 151.74, 142.30,135.07, 131.58, 131.14, 130.69, 130.38, 129.92, 123.19, 115.18, 56.94,36.87, 36.81, 36.62, 28.74.

Example 47 Synthesis ofN-(2-(N-Methyl-N-2-hydroxyethylamino)-5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted with2-(N-methylamino)ethanol (Aldrich) via Method CC to give a product thatwas coupled with 2-fluorophenyl boronic acid (Aldrich) via Method DD.The product of this coupling was converted via Method KK to give thetitle compound.

Example 48 Synthesis ofN-(5-(Piperidin-1-yl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. Piperidine (Aldrich) was sequentially converted viaMethods FFF, GGG and HHH into 4,6-dichloro-5-piperidin-1-ylpyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4,6-dichloro-5-piperidin-1-ylpyrimidine were coupled via Method III, andthe product of this coupling was sequentially converted via Methods JJJand ZZ into the title compound.

Example 49 Synthesis ofN-(5-(1-Propylbutyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4-Heptanone (Aldrich) was sequentially converted viaMethods MM, NN, OO and QQ into 4,6-dichloro-5-(1-propylbutyl)pyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4,6-dichloro-5-(1-propylbutyl)pyrimidine were coupled via Method RR, andthe product of this coupling was sequentially converted via Methods SSand ZZ to give the title compound.

Example 50 Synthesis ofN-(2-(N-Methyl-N-cyclobutylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methylcyclobutylamine (prepared by the Method of Giardina et al. J.Med. Chem. 1994, 37(21), 3482-3491) via Method CC to give a product thatwas coupled with o-tolyl boronic acid (Aldrich) via Method DD. Theproduct of this coupling was converted via Method ZZ to give the titlecompound.

Example 51 Synthesis ofN-(2-(N,N-Bis-(2-hydroxyethyl)amino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

A byproduct was isolated by chromatography of the crude product ofExample 52, and the byproduct was converted via Method KK into the titlecompound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=7.59 (d, 1H), 7.25 (d, 2H), 7.02 (d, 2H), 6.18 (d,1H), 3.76 (brs, 8H), 2.97 (s, 8H).

¹³C NMR (CD₃OD): δ=174.1, 163.7, 155, 152, 142.1, 135.2, 131.3, 123.7,99, 60.5, 56.8, 53.2, 37.5, 36.8, 36.6.

Example 52 Synthesis ofN-(2-(N,N-bis-(2-Hydroxyethyl)amino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted with diethanolamine(Aldrich) via Method CC to give a product that was coupled with o-tolylboronic acid (Aldrich) via Method DD. The product of this coupling wasconverted via Method KK to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=7.48-7.31 (m, 5H), 7.15-6.98 (m, 4H), 4.9 (m, 1H),4.63 (m, 1H), 3.83 (d, 8H), 3.1 (s, 8H), 1.9 (d, 3H).

¹³C NMR (CD₃OD): δ=173.8, 162.3, 154.6, 152.6, 140.9, 139.6, 139.4,135.9, 135.8, 132.2, 132.0, 131.4, 131.2, 131.1, 128, 123.2, 123.1,66.8, 60.6, 56.9, 56.4, 53.2, 52.8, 36.8, 36.6, 36.3; 19.5.

No Example 53 Example 54 Synthesis ofN-(2-(N-Methyl-N-phenylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted with N-methylaniline(Aldrich) via Method CC to give a product that was coupled with o-tolylboronic acid (Aldrich) via Method DD. The product of this coupling wasconverted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=7.57-6.99 (m, 14H), 4.99 (m, 1H), 3.49 (s, 3H), 3.11(m, 5H), 2.98 (s, 3H), 2.16 (s, 3H).

¹³C NMR (CD₃OD): δ=183.07, 173.72, 173.49, 162.55; 156.82, 153.97,152.07, 142.25, 141.06, 140.91, 139.53, 139.40, 135.50, 135.39, 132.21,132.16, 132.05, 131.52, 131.31, 130.53, 128.44, 128.11, 128.00, 123.13,123.04, 113.18, 56.95, 56.49, 40.02, 39.96, 37.14, 36.83, 36.65, 19.56,19.47.

Example 55 Synthesis ofN-(2-(Isopropoxy)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this coupling was sequentially converted viaMethods NNN, DD (using o-tolyl boronic acid, Aldrich) and ZZ to give thetitle compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=7.77 (bs, 1H), 7.40-6.8 (m, 9H), 6.43 (d, 0.5H) 6.27(d, 0.5H), 6.78 (m, 1H), 6.16 (m, 1H), 3.09 (s, 3H), 3.00 (s, 3H),3.40-2.80 (m, 4H), 2.20 (s, 1.5H), 1.94 (s, 1.5H), 1.23 (m, 6H).

¹³C NMR (CDCl₃): δ=176.28, 176.15, 160.03, 159.78, 154.77, 153.65,150.01, 169.97, 139.20, 137.81, 137.64, 134.39, 134.25, 130.71, 130.47,130.12, 129.15, 126.69, 126.46, 121.24, 121.18, 109.56, 56.81, 56.34,63.19, 36.90, 36.56, 36.32, 22.19, 21.99, 21.95, 19.51, 19.27.

Example 56 Synthesis ofN-(2-(N-Methyl-N-3-methylbutylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methylN-isoamylamine (Pfaltz-Bauer) via Method CC to give a productthat was coupled with o-tolyl boronic acid (Aldrich) via Method DD. Theproduct of this coupling was converted via Method ZZ to give the titlecompound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=7.6 (s, 0.5 H), 7.56 (s, 0.5H), 7.30-6.80 (m, 8H) 6.30(bm, 1H), 7.00-6.00 (br, 1H), 4.63 (m, 1H), 3.09 (s, 3H), 3.01 (s, 6H),3.80-2.80 (m, 4H), 2.13 (s, 1.5H), 1.90 (s, 1.5H), 1.61 (m, 1H), 1.51(bs, 2H), 0.96 (d, 6H).

¹³C NMR (CDCl₃): δ=174.03, 173.87, 159.28, 159.04, 154.71, 153.67,150.00, 142.10, 137.81, 137.53, 134.39, 134.22, 130.78, 130.58, 130.13,128.96, 126.52, 126.30, 121.19, 121.13, 110.11, 109.91, 56.80, 56.40,48.75, 36.55, 36:33, 35.80, 25.92, 22.54, 22.48, 19.53, 19.34.

Example 57 Synthesis ofN-(2-(N-Methylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted with N-methylamine(Aldrich) via Method CC to give a product that was coupled with o-tolylboronic acid (Aldrich) via Method DD. The product of this coupling wasconverted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=10.0-8.0 (br, 1H), 9.42 (bs, 1H), 8.24 (s, 1H),7.4-6.8 (m, 10H), 5.93 (m, 1H), 4.85 (m, 1H), 3.2-2.8 (m, 1H), 3.37 (m,1H), 3.12 (s, 1.5H), 3.11 (s, 1.5H), 3.03 (s, 1.5H), 3.02 (s, 1.5H),2.95 (s, 3H), 2.13 (s, 1.5H), 1.83 (s, 1.5H).

Example 58 Synthesis ofN-(2-(2-tolyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB: The product of this reaction was reacted with o-tolyl boronicacid (Aldrich) via Method KKK. The product of this coupling wasconverted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=8.14 (d, 1H), 7.68 (d, 1H), 7.4-6.8 (m, 12H), 5.42 (m,1H), 4.94 (m, 1H), 3.11 (s, 3H), 3.02 (s, 3H), 3.4-2.8 (m, 2H), 2.49 (s,3H), 2.11 (s, 1.5H), 1.91 (s, 1.5H).

Example 59 Synthesis ofN-(2-(N-Methyl-N-2-hydroxyethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted with2-(methylamino)-ethanol (Aldrich) via Method CC to give a product thatwas coupled with o-tolyl boronic acid (Aldrich) via Method DD. Theproduct of this coupling was converted via Method ZZ to give the titlecompound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=7.4-6.94 (m, 4H), 4.82 (m, 1H), 3.8 (brs, 4H),3.23/3.26 (s, rotamers, 3H), 2.98/3.7 (s, rotamers, 6H), 1.93/2.14 (s,rotamers, 3H).

Example 60 Synthesis ofN-(2-(N-Methyl-N-2-methylpropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into. L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted with N-methylisobutylamine (Aldrich) via Method CC to give a product that was coupledwith o-tolyl boronic acid (Aldrich) via Method DD. The product of thiscoupling was converted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=10.5-9.8 (br, 1H), 7.63 (d, 1H), 7.3-6.8 (m, 8H), 6.35(m, 1H), 4.65 (m, 1H), 3.6-2.8 (m, 4H), 3.08 (s, 3H), 3.01 (s, 6H), 2.13(s, 1.5H), 2.06 (bs, 1H), 1.25 (s, 1.5H), 0.9 (s, 6H).

¹³C NMR (CDCl₃): δ=174.13, 173.97, 159.17, 158.9, 154.7, 153.99, 149.96,142.00, 137.76, 137.53, 134.50, 134.33, 130.80, 130.58, 130.15, 128.95,126.51, 126.30, 121.15, 121.11, 110.25, 109.99, 57.46, 56.90, 56.51,36.89, 36.55, 36.32, 27.08, 19.87, 19.53, 19.38.

Example 61 Synthesis ofN-(2-(N-Methyl-N-propylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methyl-N-propylamine (Aldrich) via Method CC to give a product thatwas coupled with o-tolyl boronic acid (Aldrich) via Method DD. Theproduct of this coupling was converted via Method ZZ to give the titlecompound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=10.5-9.5 (br, 1H), 7.6 (d, 1H), 7.38-6.7 (m, 8H), 6.3(m, 1H), 4.7 (m, 1H), 3.7-3.0 (m, 4H), 3.09 (s, 3H), 3.01 (s, 6H), 2.13(s, 1.5H), 1.92 (s, 1.5H), 1.59 (bs, 2H), 0.89 (bs, 3H).

¹³C NMR (CDCl₃): δ=174.22, 174.06, 159.26, 159.0, 154.7, 153.76, 149.97,142.22, 137.78, 137.53, 134.53, 134.36, 130.80, 130.73, 130.51, 130.12,128.93, 126.50, 126.30, 121.16, 121.10, 110.13, 109.87, 56.90, 56.52,51.72, 36.55, 36.33, 35.96, 20.45, 19.56, 19.37, 11.06.

Example 62 Synthesis ofN-(2-(N,N-Dimethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN,N-dimethylamine (Aldrich) via Method CC to give a product that wascoupled with o-tolylboronic acid (Aldrich) via Method DD. The product ofthis coupling was converted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=11.0-9.5 (br, 1H), 7.62 (d, 1H), 7.3-6.8 (m, 8H), 6.22(m, 1H), 4.72 (m, 1H), 3.5-3.0 (m, 2H), 3.8 (s, 6H), 3.01 (s, 3H), 2.12(s, 1.5H), 1.94 (s, 1.5H).

¹³C NMR (CDCl₃): δ=174.49, 174.3, 159.4, 158.93, 154.72, 149.93, 140.30,137.75; 137.60, 134.67, 134.50, 130.92, 130.80, 130.51, 130.11, 128.87,126.48, 126.32, 121.15, 121.08, 109.87, 109.69, 56.86, 56.49, 37.51,36.87, 36.55, 36.34, 19.50, 19.38.

Example 63 Synthesis ofN-(2-(N-Methyl-N-cyclohexylamino)-5-(3-pyridyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methyl-N-cyclohexylamine (Aldrich) via Method CC to give a productthat was coupled with 3-pyridyl boronic acid 1,3-propanediol cyclicester (Lancaster Synthesis) via Method DD. The product of this couplingwas converted via Method HH to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.83-8.78 (m, 1H), 8.56 (brs, 1H), 8.09-7.95 (m, 2H),7.76-7.73 (m, 1H), 7.22 (d, 2H), 7.06 (d, 2H), 4.85 (m, 1H), 3.45-3.38(m, 1H), 3.18-3.11 (m, 4H), 3.06 (s, 3H), 2.99 (sm, overlapping 4H),1.92 (m, 2H), 1.76-1.57 (m, 8H).

¹³C NMR (CD₃OD): δ=173.7, 161.5, 161.4, 160.9, 157.0, 152.0, 146.0,145.7, 145.6, 143.3, 136.0, 132.2, 131.3, 128.1, 123.4, 107.8, 57.8,57.4, 36.8, 36.6, 36.1, 30.6, 30.0, 26.4, 26.2.

Example 64 Synthesis ofN-(5-(2-Phenyl-2,2-difluoroethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester.1-Trifluoromethanesulfonyloxy-2,2-difluoro-2-phenylethane wassequentially converted via Methods LL, OO and QQ into4,6-dichloro-5-(2,2-difluoro-2-phenylethyl)pyrimidine.L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butyl ester and4,6-dichloro-5-(2,2-difluoro-2-phenylethyl)pyrimidine were coupled viaMethod RR, and the product of this coupling was sequentially convertedvia Methods TT and ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.37 (s, 1H), 7.79 (s, 1H), 7.44 (s, 5H), 7.25 (d,2H), 6.98 (d, 2H), 5.07 (dd, 1H), 3.62-3.32 (m, 3H), 3.14 (dd, 1H) 3.08(s, 3H), 2.96 (s, 3H).

Example 65 Synthesis ofN-(5-(2-Phenyl-2,2-difluoroethyl)-6-chloropyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester.1-Trifluoromethanesulfonyloxy-2,2-difluoro-2-phenylethane wassequentially converted via Methods LL, OO and QQ into4,6-dichloro-5-(2,2-difluoro-2-phenylethyl)pyrimidine.L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butyl ester and4,6-dichloro-5-(2,2-/difluoro-2-phenylethyl)pyrimidine were, coupled viaMethod RR, and the product of this coupling was converted via Method ZZto give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.18 (s, 1H), 7.42-7.41 (m, 5H), 7.26 (d, 2H), 7.0 (d,2H), 5.03 (dd, 1H), 3.72-3.45 (m, 2H), 3.34 (dd, 1H), 3.19 (dd, 1H),3.08 (s, 3H), 2.96 (s, 3H).

Example 66 Synthesis ofN-(5-(2-Phenylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

4(3H)-Pyrimidinone (Aldrich) was sequentially converted via Methods Nand O into 4-chloro-5-iodopyrimidine. L-Phenylalanine tert-butyl esterhydrochloride (Bachem) and 4-chloro-5-iodopyrimidine were coupled viaMethod P. The product of this reaction was converted via Method W to aproduct that was sequentially converted via Methods X and HH to give thetitle compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.55 (d, 1H), 7.64 (d, 1H), 7.35-7.19 (m, 8H),7.01-6.98 (m, 2H), 5.46-5.41 (m, 1H), 5.34-3.60 (m, 1H), 3.29-3.23 (m,1H), 2.94-2.75 (m, 4H).

¹³C NMR (CD₃OD): δ=174.3, 164.3, 151.5, 141.8, 141.7, 139.2, 131.0,130.6, 130.5, 130.4, 128.9, 128.4, 120.6, 57.8, 38.4, 34.0, 30.7.

Example 67 Synthesis ofN-(2-(N-Methyl-N-cyclohexylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methyl-N-cyclohexylamine (Aldrich) via Method CC to give a productwhich was sequentially converted via Methods MMM and ZZ to give thetitle compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=11.20 (bs, 2H), 8.44 (s, 1H), 7.76 (bs, 1H), 7.50 (br,1H), 7.18 (d, 2H), 6.96 (d, 2H), 5.91 (bs, 1H), 4.83 (bs, 1H), 4.53 (br,1H), 3.20 (m, 2H), 3.08 (s, 3H), 2.98 (s, 6H), 2.00-1.00 (m, 10H).

¹³C NMR (CDCl₃): δ=176.18, 171.50, 167.75, 162.44, 156.31, 154.49,151.52, 135.83, 131.61, 122.85, 58.04, 56.87, 38.02, 37.79, 31.16,31.00, 26.68.

Example 68 Synthesis ofN-(5-Propylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O into 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P, and the product ofthis coupling was sequentially converted via Methods II, JJ and KK togive the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.51 (s, 1H), 7.97 (s, 1H), 7.26 (d, 2H), 6.97 (d,2H), 5.36 (m, 1H), 3.51 (m, 1H), 3.23 (m, 1H), 3.16 (s, 3H), 2.95 (s,3H), 2.47 (m, 2H), 1.57 (m, 2H), 0.99 (m, 3H).

¹³C NMR (CD₃OD): δ=173.48, 163.61, 151.97, 150.75, 140.68, 135.74,133.14, 131.30, 123.02, 120.85, 56.96, 36.99, 36.76, 36.58, 29.87,21.02, 13.67.

Example 69 Synthesis ofN-(5-(2-Methoxyphenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O to 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P and the coupledproduct was reacted with 2-methoxyphenyl boronic acid (LancasterSynthesis) via Method Q. The product of this coupling was converted viaMethod HH to give the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.64 (s, 1H), 8.05 (s, 1H), 7.61-7.55 (m, 1H),7.27-7.13 (m, 5H), 6.99 (d, 2H), 5.36-5.32 (m, 1H), 3.73 (s, 3H),3.46-3.40 (m, 1H), 4.20-3.13 (m, 4H), 3.02 (s, 3H).

¹³C NMR (CD₃OD): δ=173.8, 163.5, 159.5, 157.5, 152.8, 152.1, 143.0,135.9, 134.2, 133.9, 132.2, 123.8, 123.4, 120.5, 120.0, 113.7, 57.5,57.1, 37.9, 37.7, 37.5.

Example 70 Synthesis ofN-(5-(2-Fluorophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O into 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P and the coupledproduct was reacted with 2-fluorophenyl boronic acid (LancasterSynthesis) via Method Q. The product of this coupling was converted viaMethod HH to give the title compound.

Example 71 Synthesis ofN-(2-(N-Methyl-N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methyl-N-isopropylamine (Aldrich) via Method CC to give a product thatwas coupled with o-tolyl boronic acid (Aldrich) via Method DD. Theproduct of this coupling was converted via Method ZZ to give the titlecompound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=10.5-9.5 (br, 1H), 7.59 (d, 1H), 7.30-6.70 (m, 8H),6.3 (m, 1H), 4.92 (bs, 1H), 4.7 (m, 1H), 3.50-3.0 (m, 2H), 3.08 (s, 3H),3.00 (s, 3H), 2.83 (s, 3H), 2.13 (s, 1.5H), 1.93 (s, 1.5H) 1.15 (d, 6H).

¹³C NMR (CDCl₃): δ=174.31, 174.15, 159.21, 158.95, 154.70, 153.41,149.92, 141.98, 137.79, 137.56, 134.59, 134.41, 130.59, 130.17, 128.95,126.51, 126.32, 121.15, 110.26, 110.02, 56.87, 56.50, 46.86, 36.82,36.55, 36.31, 28.18, 19.50, 19.39.

Example 72 Synthesis ofN-(2-(N-Isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

Tyrosine tert-butyl ester-(Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted with isopropylamine(Aldrich) via Method CC to give a product that was coupled with o-tolylboronic acid (Aldrich) via Method DD. The product of this coupling wasconverted via Method ZZ to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=9.57 (s, 1H), 8.31 (s, 1H), 7.40-6.80 (m, 8H), 6.19(m, 1H), 4.79 (m, 1H), 4.15 (m, 1H), 3.4-3.0 (m, 2H), 3.10 (s, 3H), 3.01(s, 3H), 2.16 (s, 1.5H), 1.41 (s, 1.5H), 1.24 (s, 6H).

¹³C NMR (CDCl₃): δ=176.07, 175.8, 166.23, 160.23, 159.99, 154.79,153.50, 158.06, 139.38, 137.86, 137.66, 134.10, 133.93, 130.77, 130.61,130.26, 130.01, 129.25, 126.71, 126.50, 121.46, 121.36, 109.59, 109.37,56.77, 56.22, 43.31, 36.57, 36.34, 22.12, 21.96, 19.47, 19.22.

No Examples 73-77 Example 78 Synthesis ofN-(5-(2-Phenylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanineIsopropyl Ester

L-Tyrosine was sequentially converted via Methods LLL, UU, VV and WWinto L-4-(N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester.4(3H)-Pyrimidinone (Aldrich) was sequentially converted via Methods Nand O to 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine isopropyl ester and4-chloro-5-iodopyrimidine were coupled via Method P, and the coupledproduct was converted via Method OOO to a product, which was convertedvia Method X to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=8.50 (s, 1H), 7.91 (s, 1H), 7.31-7.20 (m, 3H),7.42-7.00 (m, 6H), 5.19-5.17 (m, 1H), 5.08-5.02 (m, 2H), 3.23-3.17 (m,2H), 3.06 (s, 3H), 2.99 (s, 3H), 2.83-2.78 (m, 2H), 2.65-2.60 (m, 2H),1.75-1.23 (m, 6H).

¹³C NMR (CDCl₃): δ=171.8, 159.2, 156.7, 153.5, 150.7, 140.5, 130.3,128.7, 128.5, 126.4, 121.8, 117.1, 69.4, 54.2, 36.9, 36.6, 36.5, 33.6,29.8, 21.7, 21.6.

Example 79 Synthesis ofN-(3-(N-Methyl-N-4-toluenesulfonylamino)pyrazin-2-yl)-L-phenylalanineIsopropyl Ester

L-Phenylalanine (Aldrich) was converted via Method LLL toL-phenylalanine isopropyl ester hydrochloride. 2,3-Dichloropyrazine(Lancaster) was converted via Method QQQ and RRR into2-chloro-3-nitropyrazine. L-Phenylalanine isopropyl ester hydrochlorideand 2-chloro-3-nitropyrazine were coupled via Method BBB, and theproduct of this coupling was sequentially converted via Methods CCC, DDDand EEE to give the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=7.91 (d, 1H), 7.59 (d, 2H), 7.51 (d, 1H), 7.31-7.23(m, 7H), 6.08 (d, 1H), 5.01-4.97 (m, 1H), 4.92-4.89 (m, 1H) 3.24 (d,2H), 2.97 (s, 3H), 2.43 (s, 3H), 1.21-1.12 (m, 6H).

¹³C NMR (CDCl₃): δ=167.32, 147.440, 139.85, 137.38, 133.25, 131.98,128.68, 126.17, 125.17, 125.06, 124.41, 124.11, 122.58, 64.38, 50.65,33.49, 32.41, 17.16, 17.08, 17.03.

Example 80 Synthesis ofN-(5-(2-Phenylethyl)pyrimidin-4-yl)-L-phenylalanine Isopropyl Ester

L-Phenylalanine isopropyl ester hydrochloride was prepared by MethodLLL. 4(3H)-Pyrimidinone (Aldrich) was sequentially converted via MethodsN and O to 4-chloro-5-iodopyrimidine. L-Phenylalanine isopropyl esterhydrochloride and 4-chloro-5-iodopyrimidine were coupled via Method Pand the coupled product sequentially converted via Methods OOO and X togive the title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=8.51 (s, 1H), 7.92 (s, 1H), 7.30-7.15 (m, 5H),7.14-7.06 (m, 4H), 5.16 (m, 1H), 5.09-5.01 (m, 2H), 3.31-3.16 (m, 2H),2.79-2.74 (m, 2H), 2.62-2.57 (m, 2H), 1.15-1.20 (m, 6H).

¹³C NMR (CDCl₃): δ=171.7, 159.1, 156.7, 153.5, 140.5, 136.1, 129.4,128.6, 128.5, 128.3, 127.1, 126.4, 117.0, 69.3, 54.2, 37.6, 33.7, 30.0,21.7, 21.6.

No Example 81 Example 82 Synthesis ofN-(5-(N-Methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, XX and YY intoL-4-(4-methylpiperazin-1-ylcarbonyloxy)-phenylalanine tert-butyl ester.5-Nitrouracil (Aldrich) was converted via Method AAA into2,4-dichloro-5-nitropyrimidine.L-4-(4-Methylpiperazin-1-ylcarbonyloxy)phenylalanine tert-butyl esterand 2,4-dichloro-5-nitropyrimidine were coupled via Method BBB, and theproduct of this coupling was sequentially converted via Methods CCC, DDD(using 3-chlorosulfonylpyridine), EEE and ZZ to give the title compound.

No Examples 83-84 Example 85 Synthesis ofN-(2-(N-Methyl-N-cyclohexylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N dimethylcarbamyloxy)-phenylalaninetert-butyl ester. L-4-(N,N-Dimethylcarbamyloxy)-phenylalanine tert-butylester and 5-bromo-2,4-dichloropyrimidine (Aldrich) were coupled viaMethod BB. The product of this reaction was reacted withN-methyl-N-cyclohexylamine (Aldrich) via Method CC to give a productthat was coupled with o-tolyl boronic acid (Aldrich) via Method DD. Theproduct of this coupling was converted via Method ZZ to give the titlecompound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=10.0-9.08 (br, 1H), 7.55 (s, 0.5H), 7.52 (s, 0.5H),7.20-6.31 (m, 8H), 6.36 (br, 1H), 4.69 (m, 2H), 3.40 (m, 1H), 3.15 (m,1H), 3.06 (brs, 3H), 2.98 (brs, 3H), 2.84 (brs, 3H), 2.11 (s, 1.5H),2.00-1.00 (brm, 11.5 H).

¹³C NMR (CDCl₃): δ=164.10, 159.20, 159.00, 154.79, 153.50, 150.03,137.68, 137.48, 134.48, 130.66, 130.22, 129.01, 126.62, 126.40, 121.16,110.20, 57.00, 56.58, 55.50, 36.62, 36.39, 29.91, 29.52, 25.41, 19.60,19.65.

No Examples 86-87 Example 88 Synthesis ofN-(5-(2-Tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanineIsopropyl Ester

L-Tyrosine (Aldrich) was sequentially converted via Methods LLL, UU, VVand WW into. L-4-(N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester.4(3H)-Pyrimidinone (Aldrich) was sequentially converted via Methods Nand O into 4-chloro-5-iodopyrimidine.L-4-(N,N-dimethylcarbamyloxy)-phenylalanine isopropyl ester and4-chloro-5-iodopyrimidine were coupled via Method P. The product of thiscoupling was reacted with o-tolyl boronic acid via Method Q to affordthe title compound.

Physical data were as follows:

¹H NMR (CDCl₃): δ=8.58 (s, 1H), 7.99 (s, 1H), 7.76-7.33 (m, 3H), 7.13(m, 0.5H), 7.03-6.95 (m, 4H), 4.97-4.87 (m, 3H), 3.08-2.99 (m, 8H), 2.09(s, 2H), 1.92 (s, 1.5H), 1.24-1.12 (m, 6H).

¹³C NMR (CDCl₃): δ=171.4, 171.2, 158.8, 158.5, 157.5, 154.7, 153.6,153.5, 150.5, 137.1, 137.0, 132.9, 132.3, 132.5, 130.8, 130.7, 130.0,129.8, 129.7, 128.9, 126.6, 126.5, 121.6, 119.5, 119.4, 69.0, 54.5,54.0, 36.9, 36.8, 36.6, 36.4, 21.65 21.60, 19.3, 19.2.

Example 89 Synthesis ofN-(5-(3-Nitrophenyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O to 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P, and the coupledproduct was reacted with 3-nitrophenyl boronic acid (Aldrich) via MethodT. The product of this coupling was converted via Method HH to give thetitle compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.67 (s, 1H), 8.41-8.38 (m, 1H), 8.28-8.27 (m, 1H),8.17 (s, 1H), 7.82-7.77 (m, 1H), 7.67-7.65 (m, 1H), 7.20 (d, 2H), 7.02(d, 2H), 5.33-5.28 (m, 1H), 3.47-3.411 (m, 1H), 3.12-3.04 (m, 4H), 2.97(s, 3H).

¹³C NMR (CD₃OD): δ=173.7, 163.6, 157.6, 152.8, 152.7, 151.2, 143.8,137.4, 136.3, 134.2, 133.1, 132.2, 126.7, 126.3, 124.0, 120.3, 58.0,37.7, 37.6, 37.5.

No Example 90 Example 91 Synthesis ofN-(5-(3-Pyridyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O to 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P, and the coupledproduct was reacted with 3-pyridyl boronic acid 1,3-propanediol cyclicester (Lancaster Synthesis) via Method Q. The product of this couplingwas converted via Method HH to give the title compound.

Example 92 Synthesis ofN-(5-(2-Phenylethyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O into 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P. The product of thisreaction was sequentially converted via Methods W, X, and HH to give thetitle compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.52 (s, 1H), 7.67 (s, 1H), 7.34-7.19 (m, 5H),7.08-6.99 (m, 4H), 5.50-5.42 (m, 1H), 5.59-5.53 (m, 1H), 3.26-3.21 (m,1H), 3.09 (s, 2H), 2.99 (s, 3H), 2.94-2.85 (m, 4H).

¹³C NMR (CD₃OD): δ=174.2, 164.2, 157.5, 152.7, 151.4, 141.8, 141.7,136.5, 132.0, 130.5, 130.4, 128.4, 123.8, 120.5, 57.8, 37.9, 37.6, 37.5,34.1, 30.6.

Example 93 Synthesis ofN-(2-N,N-Dimethylamino-5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl)-L-phenylalanine

5-Nitrouracil (Aldrich) was converted via Method AAA into2,4-dichloro-5-nitropyrimidine. L-Phenylalanine tert-butyl ester(Bachem) and 2,4-dichloro-5-nitropyrimidine were coupled via Method BBB,and the product of this coupling was sequentially converted via MethodsSSS (using dimethylamine), CCC, DDD, EEE and ZZ to give the titlecompound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.15 (s, formate), 7.65 (m, 2H), 7.41 (d, 2H),7.40-7.19 (m, 5H), 7.02-6.92 (m, 1H), 4.90 (m, 1H), 3.40-3.10 (m, 2H),3.09-2.92 (m, 9H), 2.43 (s, 3H).

¹³C NMR (CD₃OD): δ=177.07, 159.64, 154.70, 152.25, 144.10, 141.97,141.33, 140.25, 132.57, 129.02, 125.21, 124.82, 123.57, 123.42, 121.88,107.64, 51.08, 33.71, 32.72, 31.76, 15.49.

Example 94 Synthesis ofN-(5-(2-Tolyl)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

L-Tyrosine tert-butyl ester (Bachem) was sequentially converted viaMethods UU, VV and WW into L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester. 4(3H)-Pyrimidinone (Aldrich) was sequentiallyconverted via Methods N and O into 4-chloro-5-iodopyrimidine.L-4-(N,N-Dimethylcarbamyloxy)phenylalanine tert-butyl ester and4-chloro-5-iodopyrimidine were coupled via Method P and the coupledproduct was reacted with o-tolyl boronic acid (Aldrich) via Method Q.The product of this coupling was converted via Method HH to give thetitle compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ=8.75-8.65 (d, 1H), 8.05-8.03 (d, 1H), 7.51-7.35 (m,3H), 7.26-7.11 (m, 3H), 7.02-6.97 (m, 2H), 5.38-5.27 (m, 2H), 3.50-3.39(m, 1H), 3.21-3.07 (m, 4H), 3.02 (s, 3H), 2.21-1.93 (s, 3H).

¹³C NMR (CD₃OD): δ=173.8, 173.6, 164.0, 163.8, 157.5, 152.7, 152.6,143.0, 142.8, 139.7, 139.5, 136.1, 135.9, 133.2, 133.0, 132.4, 132.2,132.1, 131.9, 131.1, 129.0, 128.9, 123.8, 123.7, 122.2, 122.0, 57.6,57.4, 37.8, 37.7, 37.5, 37.4, 20.3, 20.2.

Additionally, using the procedures described herein and the appropriatestarting materials, the following additional compounds can be prepared:

-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2-methoxyphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 95),-   N-(2-(N-methyl-N-isopropylamino)-5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 96),-   N-(2-(N-methyl-N-isopropylamino)-5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(2-methoxyphenyl)phenylalanine    (Example 97),-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2,6-difluorophenyl)pyrimidin-4-yl)-L-4-(2,6-difluorophenyl)phenylalanine    (Example 98),-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2-hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 99),-   N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 100),-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2-trifluoromethylphenyl)pyrimidin-4-yl)-L-4-(2-cyanophenyl)phenylalanine    (Example 101),-   N-(2-(N-methyl-N-cyclohexylamino)-5-(3-thienyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 102),-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2-thienyl)pyrimidin-4-yl)-L-4-(4-trifluoromethylphenyl)phenylalanine    (Example 103),-   N-(2-(N-methyl-N-cyclohexylamino)-5-(3-pyridyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 104),-   N-(2-(N-methyl-N-cyclohexylamino)-5-(3-nitrophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 105),-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2,6-dichlorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 106),-   N-(2-(N-methyl-N-cyclohexylamino)-5-(4-pyridyl)pyrimidin-4-yl)-L-4-(3-hydroxymethylphenyl)phenylalanine    (Example 107),-   N-(2-(N-ethyl-N-isopropylamino)-5-(2,6-dimethoxyphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 108),-   N-(2-(N-methyl-N-cyclohexylamino)-5-(2,3-dichlorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 109),-   N-(2-(N-methyl-N-ethylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2-cyanophenyl)phenylalanine    (Example 110),-   N-(2-(N-methyl-N-isopropylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(3-pyridyl)phenylalanine    (Example 111),-   N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2-cyanophenyl)phenylalanine    (Example 112),-   N-(2-(N-methyl-N-(1-methylpiperidin-4-yl)amino)-5-(2-cyanophenyl)pyrimidin-4-yl)-L-4-(2,6-difluorophenyl)phenylalanine    (Example 113),-   N-(2-(N-ethyl-N-isopropylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(o-tolyl)phenylalanine    (Example 114),-   N-(2-(N-methyl-N-4-chlorophenylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 115),-   N-(5-(N-methyl-N-2-(phenyl)ethylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    (Example 116),-   N-(5-(N-methyl-N-hexylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    (Example 117),-   N-(5-(N-methyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    (Example 118),-   N-(5-(N-methyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    (Example 119),-   N-(5-(N-methyl-N-tert-butylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    (Example 120),-   N-(5-(N-ethyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    (Example 121),-   N-(5-(N-methyl-N-2-(4-pyridyl)ethyl-pyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    (Example 122),-   N-(5-(N-methyl-N-2-(phenyl)ethylamino)pyrimidin-4-yl)-L-4-(4-(2,6-dimethoxyphenyl)phenylalanine    (Example 123),-   N-(5-(N-methyl-N-hexylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 124),-   N-(5-(N-methyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 125),-   N-(5-(N-methyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 126),-   N-(5-(N-methyl-N-tert-butylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 127),-   N-(5-(N-ethyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 128),-   N-(5-(N-methyl-N-2-(4-pyridyl)ethyl-pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine    (Example 129)-   N-(2-(N-methyl-N-cyclohexylamino)-5-ethylpyrimidin-4-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine    (Example 130).

Example 131 Synthesis ofN-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosineStep A: Preparation of 3,4-Diethyloxy-1-oxo-1,2,5-thiadiazole and3,4-Diethyloxy-1,1-dioxo-1,2,5-thiadiazole

The title intermediates were prepared according to the proceduresdescribed in R. Y. Wen et al, J Org. Chem., (1975) 40, 2743; and R. Y.Wen et al, Org Prep Proceed., (1969) 1, 255.

Step B: Preparation of4-(N,N-Di-n-hexylamino)-3-ethoxy-1,1-dioxo-1,2,5-thiadiazole

Dihexylamine (90 mg, 0.48 mmol) was added to a solution of3,4-diethyloxy-1,1-dioxo-1,2,5-thiadiazole (100 mg, 0.48 mmol) inethanol (5 mL) and the reaction stirred overnight at room temperature.The solvent was removed under reduced pressure and the residue absorbedonto silica gel; and purified by flash column chromatography (silica,hexane:EtOAc 3:1) to yield the title intermediate (120 mg, 72%).

Physical data were as follows:

MS (EI, m/e) 345.

Step C: Preparation ofN-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosinetert-Butyl Ester

A solution of4-(N,N-di-n-hexylamino)-3-ethoxy-1,1-dioxo-1,2,5-thiadiazole (400 mg,1.02 mmol) and L-tyrosine t-butyl ester (261 mg, 1.1 mmol) in EtOH (10mL) was stirred at room temperature for 36 hrs. The solvent was removedunder reduced pressure residue purified by flash column chromatography(silica, hexane:EtOAc 3:1 then 1:1) to give the title compound as awhite waxy solid (400 mg, 73%).

Physical data were as follows:

Anal. Calc'd for C₂₇H₄₄N₄O₅S.0.55EtOAc: C, 59.93; H, 8.34; N, 9.57.Found: C, 59.84; H, 8.44; N, 9.62.

Step D: Preparation ofN-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosine

The compound from Step C (100 mg, 0.19 mmol) was dissolved in formicacid and the mixture stirred at room temperature for 36 hrs. Excessformic acid was removed under reduced pressure to yield the titlecompound as a white solid (90 mg, 98%).

Physical data were as follows:

Anal. Calc'd for C₂₃H₃₆N₄O₅S: C, 57.48; H, 7.55; N_(;) 11.66.

Found: C, 57.04; H, 7.23; N, 11.38.

Example 132 Synthesis ofN-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanineStep A: Preparation ofN-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-Butyl Ester

N-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosinetert-butyl ester (180 mg, 0.34 mmol.) was dissolved in pyridine (5 ml).Dimethylcarbamoyl chloride (108 mg, 1 mmol) was added dropwise and themixture stirred at room temperature overnight. Pyridine was removedunder high vacuum (low water bath temperature), the residue absorbedonto silica gel and purified by flash column chromatography (silica,hexane:EtOAc 2:1) to yield the title compound (140 mg, 68%).

Step B: Preparation ofN-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N-dimethylcarbamyloxy)-phenylalanine

The compound from Step A (140 mg, 0.23 mmol) was dissolved in formicacid and the mixture stirred at room temperature overnight. Excessformic acid was removed under reduced pressure to yield the titlecompound as a white solid (110 mg, 87%).

Physical data were as follows:

Anal. Calc'd for C₂₆H₄₁N₅O₆S: C, 56.6; H, 7.49; N, 12.69.

Found: C, 56.67; H, 7.4; N, 12.46.

Example 133 Synthesis ofN-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanineStep A: Preparation ofN-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalaninetert-Butyl Ester

A solution ofN-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosinetert-butyl ester (500 mg, 0.93 mmol), and p-nitrophenyl chloroformate(179 mg, 0.89 mmol) in dichloromethane (20 mL) was cooled to 0° C. underan argon atmosphere. Triethylamine (235 mg, 2.32 mmol) was addeddropwise and the mixture stirred at 0° C. for 30 mins, then allowed towarm to room temperature for a further 40 mins. The mixture was recooledto 0° C. and N-methylpiperazine (90 mg, 0.89 mmol) added. The mixturewas allowed to warm to room temperature and stirred for three hours.

The mixture was diluted with diethyl ether (150 mL) and the organicsolution washed with 10% potassium carbonate solution until no furtheryellow color was produced in the aqueous phase. The organic layer wasseparated, dried (MgSO₄) and the solvent removed under reduced pressure.The residue was purified by flash column chromatography (silica,EtOAc:MeOH:Et₃N 94:5:1) to give the title compound as a pale yellow foam(310 mg, 50%).

Physical data were as follows:

Anal. Calc'd for C₃₃H₅₄N₆O₆S: C, 59.79; H, 8.21; N, 12.68.

Found: C, 59.47; H, 8.25; N, 12.49.

Step B: Preparation ofN-(4-(N,N-Di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(4-methylpiperazin-1-ylcarbonyloxy)phenylalanine

The compound from Step A (200 mg, 0.3 mmol) was dissolved in formic acid(5 mL) and the mixture stirred at room temperature for 48 hrs. Excessformic acid was removed under reduced pressure and the residuerecrystallized from EtOAc/MeOH to yield the title compound as anoff-white solid (120 mg, 67%).

Physical data were as follows:

Anal. Calc'd for C₂₉H₄₆N₆O₆S.0.75H₂O: C, 56.15; H, 7.72; N, 13.55.Found: C, 56.1; H, 7.44; N, 13.46.

Example 134 Synthesis ofN-[4-(2-(3-Methylphenylaminocarbonylamino)eth-1-ylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanineStep A: Preparation ofN-(4-Ethoxy-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosine tert-Butyl Ester

A solution of 3,4-diethyloxy-1,1-dioxo-1,2,5-thiadiazole (400 mg, 1.94nunopand L-tyrosine t-butyl ester (1.25 g, 5.2 mmol) in ethanol (25 mL)was stirred at room temperature overnight. Solvent was removed underreduced pressure and the product used in further transformations withoutfurther purification (Yield 790 mg).

Step B: Preparation of 2-(3-Methylphenylaminocarbonylamino)eth-1-ylamine

N-Boc-Ethylene diamine (800 mg, 5 mmol) and m-tolyl isocyanate (665 mg,5 mmol) were dissolved in acetonitrile and the mixture stirred at roomtemperature for 4 hrs. Solvent was removed under reduced pressure andthe residue absorbed onto silica gel; prior to purification by flashcolumn chromatography (silica, hexane:EtOAc 1:1) to yield the desiredcompound as a white solid (300 mg, 21%) (MS (+ESI, m/e) 294 (M+H)⁺). TheN-Boc protected compound (300 mg, 1.02 mmol) was dissolved in formicacid (10 ml) and the mixture stirred at room temperature overnight.Excess acid was removed to yield the formate salt of the title compoundas a white foam (210 mg).

Step C: Preparation ofN-[4-(2-(3-Methylphenylamino-carbonylamino)eth-1-ylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]-L-tyrosinetert-Butyl Ester

To a solution of N-(4-ethoxy-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosinetert-butyl ester from Step A (150 mg, 0.38 mmol) and the formate salt of2-(3-methylphenylaminocarbonylamino)eth-1-ylamine from Step B (210 mg,0.89 mmol) in ethanol (10 mL) was added triethylamine (133 mg, 1.44mmol). The reaction was stirred at room temperature overnight. Solventwas removed under reduced pressure and the residue purified by flashcolumn chromatography (silica, 5% MeOH in EtOAc) to give the titlecompound (130 mg, 91%).

Physical data were as follows:

MS (+ESI, m/e) 545 (M+H)⁺.

Step D: Preparation ofN-[4-(2-(3-Methylphenylamino-carbonylamino)eth-1-ylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

The intermediate from Step C (130 mg, 0.24 mmol) was dissolved inpyridine (5 mL). Dimethylcarbamoyl chloride (77 mg, 0.72 mmol) was addeddropwise and the mixture heated at 50° C. under an argon atmosphereovernight. Pyridine was removed under reduced pressure, the residueabsorbed onto silica gel and purified by flash column chromatography(silica, hexane:EtOAc 1:2, then 5% MeOH in EtOAc) to yield the titlecompound (140 mg, 93%).

Physical data were as follows:

MS (+ESI, m/e) 616 (M+H)⁺.

Step E: Preparation ofN-[4-(2-(3-Methylphenylamino-carbonylamino)eth-1-ylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine

The compound from Step D (120 mg, 0.19 mmol) was dissolved in formicacid (10 mL) and the mixture stirred at room temperature for 36 hrs.Excess acid was removed to yield the title compound as a pale yellowfoam (100 mg, 93%).

Physical data were as follows:

MS (+ESI, m/e) 560 (M+H)⁺.

Example 135 Synthesis ofN-(4-(N,N-Dimethylamino)-1-oxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester Step A: Preparation ofN-(4-Ethoxy-1-oxo-1,2,5-thiadiazol-3-yl)-L-tyrosine tert-Butyl Ester

A solution of 3,4-diethoxy-1-oxo-1,2,5-thiadiazole (1 g, 0.52 mmol) andL-tyrosine t-butyl ester (1.25 g, 0.52 mmol) in ethanol (25 mL) wasstirred at room temperature for 60 hr. Solvent was removed under reducedpressure and the residue purified by flash column chromatography(silica, hexane:EtOAc 1:1 to give the title intermediate (1.75 g, 88%).

Physical data were as follows:

MS (+ESI, m/e) 382 (M+H)⁺.

Step B: Preparation ofN-(4-Ethoxy-1-oxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

The intermediate from Step A (400 mg, 1.05 mmol) was dissolved inpyridine (10 mL) and dimethylcarbamoyl chloride (338 mg, 3.15 mmol) wasadded. The reaction was stirred at room temperature under an inertatmosphere overnight. TLC indicated large amounts of unreacted startingmaterial so the mixture was heated at 50° C. for a further 48 hrs.Excess pyridine was removed under reduced pressure and the residuepurified by flash column chromatography (silica, hexane:EtOAc 1:1 togive the title intermediate (280 mg, 59%).

Physical data were as follows:

MS (+ESI, m/e) 453 (M+H).

Step C: Preparation ofN-(4-(N,N-Dimethylamino)-1-oxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N-dimethylcarbamyloxy)phenylalaninetert-Butyl Ester

A 2M solution of dimethylamine in THF (5 mL, 10 mmol) was added to asolution of the compound from Step B (180 mg, 0.35 mmol) in ethanol (10mL). The reaction was stirred at room temperature overnight and solventremoved under reduced pressure. Residue was purified by flash columnchromatography (silica, EtOAc:MeOH:Et₃N 90:10:1) to give the titlecompound as a white foam (140 mg, 88%).

Physical data were as follows:

Anal. Calc'd for C₂₂₀H₂₉N₅O₅S: C, 53.2; H, 6.47; N, 15.51.

Found: C, 52.94; H, 6.18; N, 15.34.

Example 136 Synthesis ofN-(5-(2,2,2-Trifluoroethyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine

Substituting L-4-(2,6-dimethoxyphenyl)phenylalanine methyl ester fromMethod TTT for L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butylester and following the procedure described for the preparation ofExample 31 yielded the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ 8.41 (s, 1H), 8.05 (s, 1H), 7.24 (t, 1H), 7.2 (d, 2H),7.1 (d, 2H), 6.67 (d, 2H), 5.1 (dd, 1H), 3.65 (s, 61-1), 3.61-3.42 (m,2H), 3.36 (dd, 1H), 3.2 (dd, 1H).

¹³C NMR (CD₃OD): δ 175.8, 162.3, 159.2, 157.9, 155.8, 136.9, 134.4,132.2, 130.0, 129.5, 127.4, 120.9, 109.6, 105.7, 56.8, 56.2, 37.9, 32.6.

Example 137 Synthesis ofN-(2-(N-Cyclohexyl-N-methyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine

Substituting L-4-(2,6-dimethoxyphenyl)phenylalanine methyl ester fromMethod TTT for L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butylester and following the procedure described for the preparation ofExample 14 yielded the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ 7.37-7.19 (m, 5.5H), 7.09-7.02 (m, 4H), 6.94 (d,0.5H), 6.68 (d, 2H), 4.79-4.74 (m, 0.5H), 4.69-4.65 (m. 0.5H), 3.6.7 (s,3H), 3.65 (s, 3H), 3.44-3.33 (m, 1H), 3.02-2.95 (m, 4H), 2.19 (s, 1.5H),1.85-1.71 (m, 6.5H), 1:57 (m, 4H), 1.29-1.2 (br s, 1H).

Example 138 Synthesis ofN-(5-(2-Fluorophenyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine

Substituting L-4-(2,6-dimethoxyphenyl)phenylalanine methyl ester fromMethod TTT for L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butylester and following the procedure described for the preparation ofExample 70 yielded the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ 8.50 (s, 1H), 8.01 (s, 1H), 7.3-7.0 (m, 9H), 6.69 (d,2H), 5.0 (m, 1H), 3.65 (s, 6H), 3.20-3.05 (m, 2H):

¹³C NMR (CD₃OD): δ 153.2, 151.6, 147.1, 130.2, 128.6, 126.7, 126.6,126.5, 126.4, 126.3, 123.9, 123.5, 123.2, 120.5, 120.4, 111.7, 111.4,99.6, 59.3, 31.7.

Example 139 Synthesis ofN-(2-(N-Methyl-N-propyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine

Substituting L-4-(2,6-dimethoxyphenyl)phenylalanine methyl ester fromMethod TTT for L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butylester and following the procedure described for the preparation ofExample 61 yielded the title compound.

Physical data were as follows:

¹H NMR (CD₃OD): δ 10.30-8:80 (br, 1H), 7.68 (s, 0.5H), 7.63 (s, 0.5H),7.40-6.60 (m, 1H), 6.15 (m, 1H), 4.70 (m, 1H), 3.68 (s, 3H), 3.66 (s,3H), 3.80-3.00 (m, 4H), 3.07 (s, 3H), 2.12 (s, 1.5H), 2.08 (s, 1.5H),1.61 (bs, 2H), 0.87 (bs, 3H).

Example 140 Synthesis ofN-(3-Chloropyrazin-2-yl)-L-4-[1-(tert-butoxycarbonyl)piperidin-4-ylcarbonylamino]phenylalanineEthyl Ester Step A: Preparation ofN-(3-Chloropyrazin-2-yl)-L-4-nitrophenylalanine

4-Nitrophenylalanine (50 mm, 10.59 mg) were stirred in absolute ethanolcontaining 1.0 eq (1.26 g) of sodium metal. The reaction mixture wasstripped to a brown solid and the sodium salt was taken up in 200 mL ofbutanol containing 1.0 eq (7.45 g) 2,3-dichloropyrazine. The reactionmixture was refluxed overnight and the solvent was then removed underreduced pressure. The residue was taken up in ethyl acetate and washedwith water (1×), brine (1×), dried over Na₂SO₄, filtered and stripped togive 15.5 g of the title intermediate as a brown oil.

Physical data were as follows:

Analytical: MS: (+)FAB [M+H] @ M/Z 323 with 1 Cl.

Step B: Preparation of N-(3-Chloropyrazin-2-yl)-L-4-nitrophenylalanineEthyl Ester

The intermediate from Step A was suspended in 300 mL of absoluteethanol. The reaction flask was placed in an ice bath and cooled to 0°C. and HCl (g) was bubbled into reaction for 15 minutes. The gas tubewas replaced with a drying tube and the reaction mixture was warmed toroom temperature and stirred overnight. Ethanol was stripped off underreduced pressure to afford a dark brown residue which was taken up inethyl acetate and washed with sat. NaHCO₃ (2×), H₂O (1×), brine (1×),dried over Na₂SO₄, filtered and stripped to afford 1.5 g of a dark brownoil. This oil (8.0 g) was chromatographed on a silica 60 column packedin methylene chloride to provide 1.5 g (20% yield) of the titleintermediate.

Physical data were as follows:

Analytical: MS: EI M⁺ @ M/Z 350 1 Cl present.

Step C: Preparation of N-(3-Chloropyrazin-2-yl)-L-4-aminophenylalanineEthyl Ester

The intermediate from Step B (0.75 g, 0.021 mol) was placed in a Paarhydrogenation bottle with 50 mL ethanol and 0.40 g of Pd/C catalyst. Thebottle was placed on Paar shaker under 50 psi of H₂ for 3 hrs. Thereaction mixture was then filtered through a sintered glass funnel (F)and the filtered catalyst was washed with ethanol. The combinedfiltrates were stripped to a yellow oil and the oil was taken up inethyl acetate. A yellow precipitate formed and was filtered off. Thefilterate was washed with NaHCO₃ solution (1×), H₂O (1×), brine (1×),dried over. Na₂SO₄, filtered and stripped to afford the title,intermediate as a yellow oil (0.340 g, 55% yield):

Step D: Preparation ofN-(3-Chloropyrazin-2-yl)-L-4-[1-(tert-butoxycarbonyl)piperidin-4-ylcarbonylamino]phenylalanineEthyl Ester

N-Boc-piperidine 4-carboxylic acid (0.253 g, 1.0 eq., 0.0011 mol) wasstirred in 30 mL methylene chloride and reaction mixture was cooled to0° C. in ice bath. HOBt (0.224 g, 1.5 eq) was added and the mixture wasstirred for 10 minutes then the intermediate from Step C (1 eq., 0.32 g)was added. The reaction mixture was stirred for 5 minutes and then1,3-dicyclohexylcarbodiimide (0.25 g, 1.1 eq) was added. The reactionmixture was warmed to room temperature and stirred overnight. Thereaction was then filtered and the filtrate was stripped to give ayellow solid. The solid was taken up in ethyl acetate and filtered. Theethyl acetate solution was washed with 10% citric acid (1×), H₂O (1×),brine (1×), dried over Na₂SO₄, filtered and stripped to afford a yellowoil (0.630 g; MS: EI M⁺ @ M/Z 531 (1 chloro)). The yellow oil waschromatographed on a silica 60 column eluting with 3:1 hexane/ethylacetate to afford 0.097 g of the title compound. This compound may alsobe used as an intermediate for other compounds of this invention.

Physical data were as follows:

Analytical: CHN: Theory (0.5H₂0): C, 57.71; H, 6.72; N, 12.94

Found: C, 57.79; H, 6.32; N, 12.78. MS: M⁺ @ M/Z 531 (1 Chloro).

Example A In Vitro Assay for Determining Binding of Candidate Compoundsto VLA-4

An in vitro assay was used to assess binding of candidate compounds toα₄β₁ integrin. Compounds which bind in this assay can be used to assessVCAM-1 levels in biological samples by conventional assays (e.g.,competitive assays). This assay is sensitive to IC₅₀ values as low asabout 1 nM.

The activity of α₄β₁ integrin was measured by the interaction of solubleVCAM-1 with Jurkat cells (e.g., American Type Culture Collection Nos.TIB 152, TIB 153, and CRL 8163), a human T-cell line which expresseshigh levels of α₄β₁ integrin. VCAM-1 interacts with the cell surface inan α₄β₁ integrin-dependent fashion (Yednock, et al. J. Biol. Chem.,1995, 270:28740).

Recombinant soluble VCAM-1 was expressed as a chimeric fusion proteincontaining the seven extracellular domains of VCAM-1 on the N-terminusand the human IgG, heavy chain constant region on the C-terminus. TheVCAM-1 fusion protein was made and purified by the manner described byYednock, supra.

Jurkat cells were grown in RPMI 1640 supplemented with 10% fetal bovineserum, penicillin, streptomycin and glutamine as described by Yednock,supra.

Jurkat cells were incubated with 1.5 mM MnCl₂ and 5 μg/mL 15/7 antibodyfor 30 minutes on ice. Mn⁺² activates the receptor to enhance ligandbinding, and 15/7 is a monoclonal antibody that recognizes anactivated/ligand occupied conformation of α₄β₁ integrin and locks themolecule into this conformation thereby stabilizing the VCAM-1/α₄β₁integrin interaction. Yednock, et al., supra. Antibodies similar to the15/7 antibody have been prepared by other investigators (Luque, et al,1996, J. Biol. Chem. 271:11067) and may be used in this assay.

Cells were then incubated for 30 minutes at room temperature withcandidate compounds, in various concentrations ranging from 66 μM to0.01 μM using a standard 5-point serial dilution. 15 μL solublerecombinant VCAM-1 fusion protein was then added to Jurkat cells andincubated for 30 minutes on ice. (Yednock et al., supra.).

Cells were then washed two times and resuspended in PE-conjugated goatF(ab′), anti-mouse IgG Fc (Immunotech, Westbrook, Me.) at 1:200 andincubated on ice, in the dark, for 30 minutes. Cells were washed twiceand analyzed with a standard fluorescence activated cell sorter (“FACS”)analysis as described in Yednock, et al., supra.

Compounds having an IC₅₀ of less than about 15 μM possess bindingaffinity to α₄β₁.

When tested in this assay, each of the compound prepared in the aboveexamples has or is expected to have an IC₅₀ of 15 μM or less (or isexpected to be active in vivo).

Example B In Vitro Saturation Assay for Determining Binding of CandidateCompounds to α₄β₃

The following describes an in vitro assay to determine the plasma levelsneeded for a compound to be active in the Experimental AutoimmuneEncephalomyelitis (“EAE”) model, described in the next example, or inother in vivo models.

Log-growth Jurkat cells are washed and resuspended in normal animalplasma containing 20 μg/ml of the 15/7 antibody (described in the aboveexample).

The Jurkat cells are diluted two-fold into either normal plasma samplescontaining known candidate compound amounts in various concentrationsranging from 66 μM to 0.01 μM, using a standard 12 point serial dilutionfor a standard curve, or into plasma samples obtained from theperipheral blood of candidate compound-treated animals.

Cells are then incubated for 30 minutes at room temperature, washedtwice with phosphate-buffered saline (“PBS”) containing 2% fetal bovineserum and 1 mM each of calcium chloride and magnesium chloride (assaymedium) to remove unbound 15/7 antibody.

The cells are then exposed to phycoerythrin-conjugated goat F(ab′)₂anti-mouse IgG Fc (Immunotech, Westbrook, Me.), which has been adsorbedfor any non-specific cross-reactivity by co-incubation with 5% serumfrom the animal species being studied, at 1:200 and incubated in thedark at 4° C. for 30 minutes.

Cells are washed twice with assay medium and resuspended in the same.They are then analyzed with a standard fluorescence activated cellsorter (“FACS”) analysis as described in Yednock et al. J. Biol. Chem.,1995, 270:28740.

The data is then graphed as fluorescence versus dose, e.g., in a normaldose-response fashion. The dose levels that result in the upper plateauof the curve represent the levels needed to obtain efficacy in an invivo model.

This assay may also be used to determine the plasma levels needed tosaturate the binding sites of other integrins, such as the α₉β₁integrin, which is the integrin most closely related α₄β₁ (Palmer et al,1993, J. Cell Bio., 123:1289). Such binding is predictive of in vivoutility for inflammatory conditions mediated by α₉β₁ integrin, includingby way of example, airway hyper-responsiveness and occlusion that occurswith chronic asthma, smooth muscle cell proliferation inatherosclerosis, vascular occlusion following angioplasty, fibrosis andglomerular scarring as a result of renal disease, aortic stenosis,hypertrophy of synovial membranes in rheumatoid arthritis, andinflammation and scarring that occur with the progression of ulcerativecolitis and Crohn's disease.

Accordingly, the above-described assay may be performed with a humancolon carcinoma cell line, SW 480 (ATTC #CCL228) transfected with cDNAencoding α₉ integrin (Yokosaki et al., 1994, J. Biol. Chem., 269:26691),in place of the Jurkat cells, to measure the binding of the α₉β₁integrin. As a control, SW 480 cells which express other α and β₁subunits may be used.

Accordingly, another aspect of this invention is directed to a methodfor treating a disease in a mammalian patient, which disease is mediatedby α₉β₁, and which method comprises administering to said patient atherapeutically effective amount of a compound of this invention. Suchcompounds are preferably administered in a pharmaceutical compositiondescribed herein above. Effective daily dosing will depend upon the age,weight, condition of the patient which factors can be readilyascertained by the attending clinician. However, in a preferredembodiment, the compounds are administered from about 20 to 500 μg/kgper day.

Example C In Vivo Evaluation

The standard multiple sclerosis model, Experimental Autoimmune (orAllergic) Encephalomyelitis (“EAE”), was used to determine the effect ofcandidate compounds to reduce motor impairment in rats or guinea pigs.Reduction in motor impairment is based on blocking adhesion betweenleukocytes and the endothelium and correlates with anti-inflammatoryactivity in the candidate compound. This model has been previouslydescribed by Keszthelyi et al., Neurology, 1996, 47:1053-1059, andmeasures the delay of onset of disease.

Brains and spinal cords of adult Hartley guinea pigs were homogenized inan equal volume of phosphate-buffered saline. An equal volume ofFreund's complete adjuvant (100 mg mycobacterium tuberculosis plus 10 mlFreund's incomplete adjuvant) was added to the homogenate. The mixturewas emulsified by circulating it repeatedly through a 20 ml syringe witha peristaltic pump for about 20 minutes.

Female Lewis rats (2-3 months old, 170-220 g) or Hartley guinea pigs (20day old, 180-200 g) were anesthetized with isoflurane and threeinjections of the emulsion, 0.1 ml each, were made in each flank. Motorimpairment onset is seen in approximately 9 days.

Candidate compound treatment began on Day 8, just before onset ofsymptoms. Compounds were administered subcutaneously (“SC”), orally(“PO”) or intraperitoneally (“IP”). Doses were given in a range of 10mg/kg to 200 mg/kg, bid, for five days, with typical dosing of 10 to 100mg/kg SC, 10 to 50 mg/kg PO, and 10 to 100 mg/kg IP.

Antibody GG5/3 against α₄β₁ integrin (Keszthelyi et al., Neurology,1996, 47:1053-1059), which delays the onset of symptoms, was used as apositive control and was injected subcutaneously at 3 mg/kg on Day 8 and11.

Body weight and motor impairment were measured daily. Motor impairmentwas rated with the following clinical score:

0 no change 1 tail weakness or paralysis 2 hindlimb weakness 3 hindlimbparalysis 4 moribund or dead

A candidate compound was considered active if it delayed the onset ofsymptoms, e.g., produced clinical scores no greater than 2 or slowedbody weight loss as compared to the control.

Example D Asthma Model

Inflammatory conditions mediated by α₄β₁ integrin include, for example,airway hyper-responsiveness and occlusion that occurs with chronicasthma. The following describes an asthma model which can be used tostudy the in vivo effects of the compounds of this invention for use intreating asthma.

Following the procedures described by Abraham et al, J. Clin. Invest,93:776-787 (1994), and Abraham et al, Am J. Respir Crit. Care Med,156:696-703 (1997), both of which are incorporated by reference in theirentirety. Compounds of this invention are formulated into an aerosol andadministered to sheep which are hypersensitive to Ascaris suum antigen.Compounds which decrease the early antigen-induced bronchial responseand/or block the late-phase airway response, e.g., have a protectiveeffect against antigen-induced late responses and airwayhyper-responsiveness (“AHR”), are considered to be active in this model.

Allergic sheep which are shown to develop both early and late bronchialresponses to inhaled Ascaris suum antigen are used to study the airwayeffects of the candidate compounds. Following topical anesthesia of thenasal passages with 2% lidocaine, a balloon catheter is advanced throughone nostril into the lower esophagus. The animals are then intubatedwith a cuffed endotracheal tube through the other nostril with aflexible fiberoptic bronchoscope as a guide.

Pleural pressure is estimated according to Abraham (1994). Aerosols (seeformulation below) are generated using a disposable medical nebulizerthat provides an aerosol with a mass median aerodynamic diameter of 3.2μm as determined with an Andersen cascade impactor. The nebulizer isconnected to a dosimeter system consisting of a solenoid valve and asource of compressed air (20 psi). The output of the nebulizer isdirected into a plastic T-piece, one end of which is connected to theinspiratory port of a piston respirator. The solenoid valve is activatedfor 1 second at the beginning of the inspiratory cycle of therespirator. Aerosols are delivered at V_(T) of 500 ml and a rate of 20breaths/minute. A 0.5% sodium bicarbonate solution only is used as acontrol.

To assess bronchial responsiveness, cumulative concentration-responsecurves to carbachol can be generated according to Abraham (1994).Bronchial biopsies can be taken prior to and following the initiation oftreatment and 24 hours after antigen challenge. Bronchial biopsies canbe preformed according to Abraham (1994).

An in vitro adhesion study of alveolar macrophages can also be performedaccording to Abraham (1994), and a percentage of adherent cells iscalculated.

Aerosol Formulation

A solution of the candidate compound in 0.5% sodium bicarbonate/saline(w/v) at a concentration of 30.0 mg/mL is prepared using the followingprocedure:

A. Preparation of 0.5% Sodium Bicarbonate/Saline Stock Solution: 100.0mL

Ingredient Gram/100.0 mL Final Concentration Sodium Bicarbonate 0.5 g0.5% Saline q.s. ad 100.0 mL q.s. ad 100%

Procedure:

1. Add 0.5 g sodium bicarbonate into a 100 mL volumetric flask.

2. Add approximately 90.0 mL saline and sonicate until dissolved.

3. Q.S. to 100.0 mL with saline and mix thoroughly.

B. Preparation of 30.0 mg/mL Candidate Compound: 10.0 mL

Ingredient Gram/10.0 mL Final Concentration Candidate Compound 0.300 g30.0 mg/mL 0.5% Sodium q.s. ad 10.0 mL q.s ad 100% Bicarbonate/SalineStock Solution

Procedure:

1. Add 0.300 g of the candidate compound into a 10.0 mL volumetricflask.

2. Add approximately 9.7 mL of 0.5% sodium bicarbonate/saline stocksolution.

3. Sonicate until the candidate compound is completely dissolved.

4. Q.S. to 10.0 TriL with 0.5% sodium bicarbonate/saline stock solutionand mix thoroughly.

Using a conventional oral formulation, compounds of this invention wouldbe active in this model.

Example E Allograft Model

Allograft rejection, associated with infiltration of inflammatory cells,is the leading obstacle to long-term allograft survival. Cell surfaceadhesion molecules facilitate alloantigen recognition in vitro and maybe critical for lymphocyte traffic in vivo. The following describes amodel which can be used to study the in vivo effects of the compounds ofthis invention in the control of allograft rejection.

The following procedures are described in Coito et al., Transplantation(1998) 65(6):699-706 and in Korom et al., Transplantation (1998)65(6):854-859, both of which are incorporated by reference in theirentirety.

Following the procedures described in Coito and Korom, male adult ratsweighing approximately 200-250 g are used in this model. Lewis rats areused as the recipients of cardiac allografts from Lewis X Brown Norwayrats. Hearts are transplanted into the abdominal great vessels usingstandard microvascular techniques.

A candidate compound is administered to the transplant recipient in asuitable pharmaceutical carrier for a 7-day course of treatment startingthe day of the engraftment. Doses range from 0.3 to 30 mg/kg/day.Control recipients receive the pharmaceutical carrier only. The rats areeuthanized and their cardiac allografts are analyzed as described inCoito and Korom.

Using conventional formulations, compounds of this invention would beactive in this model.

1.-74. (canceled)
 75. A compound of formula Ha:

or a pharmaceutically acceptable salt thereof, wherein ring A forms apyrazine ring, optionally substituted with 1 or 2 substituents selectedfrom the group consisting of R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷,R¹⁰⁸, R¹⁰⁹, R¹¹⁰, alkoxy, substituted alkoxy, amino, substituted aminoand halogen, R³ is —(CH₂)_(x)—Ar—R⁹, wherein Ar is R¹⁰⁷ or R¹⁰⁹; x is aninteger from 0 to 4; and R⁹ is selected from the group consisting ofacyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, thioamidino,thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl,oxysulfonylamino and oxysulfonyl; R^(3′) is hydrogen; Q is —NR⁴—,wherein R⁴ is hydrogen or R¹⁰¹; R⁵ is selected from the group consistingof R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹,R¹¹², R¹¹⁵ and R¹¹⁶; R⁶ is selected from the group consisting ofhydrogen, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰,R¹¹⁵ and R¹¹⁶; and X is selected from the group consisting of hydroxyl,alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy,substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy,aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy and —NR″R″, wherein each R″is independently selected from the group consisting of hydrogen, R¹⁰¹,R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹¹⁰, R¹¹¹ and R¹¹², whereinR¹⁰¹ is alkyl of from 1 to 10 carbon atoms; R¹⁰² is substituted alkyl offrom 1 to 10 carbon atoms, having from 1 to 5 substituents selected fromthe group consisting of (1) R²⁰⁰; (2) unsymmetric di-substituted amineshaving different substituents selected from the group consisting ofR¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (3) amino groupsblocked by blocking groups selected from the group consisting oftert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)R³⁰⁰; R¹⁰³ is cycloalkyl of from 3 to 8 carbon atoms; R¹⁰⁴ issubstituted cycloalkyl of from 3 to 8 carbon atoms, having from 1 to 5substituents selected from the group consisting of (1) R²⁰⁰; (2) oxo(═O); (3) thioxo (═S); (4) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (5) amino groups blocked byblocking groups selected from tert-butyloxycarbonyl (Boc),carbobenzyloxy (Cbz) and formyl; and (6) R³⁰⁰; R¹⁰⁵ is heterocyclicreferring to a saturated or unsaturated group having from 1 to 10 carbonatoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur andoxygen, and having a single ring or multiple fused rings, wherein infused ring systems one or more of the rings can be aryl (R¹⁰⁷) orheteroaryl (R¹⁰⁹); R¹⁰⁶ is substituted heterocyclic of from 1 to 10carbon atoms and from 1 to 4 heteroatoms, substituted with from 1 to 3substituents selected from the group consisting of (1) R²⁰⁰; (2) oxo(═O); (3) thioxo (═S); (4) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (5) amino groups blocked byblocking groups selected from tert-butyloxycarbonyl (Boc),carbobenzyloxy (Cbz) and formyl; and (6) R³⁰⁰; R¹⁰⁷ is aryl, whereinaryl is an unsaturated aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring or multiple condensed rings, wherein thecondensed rings may or may not be aromatic; R¹⁰⁸ is substituted aryl,wherein substituted aryl is aryl substituted with from 1 to 3substituents selected from the group consisting of (1) R²⁰¹; (2)unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of R¹⁰¹, R¹⁰², R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹and R¹¹⁰; (3) amino groups blocked by blocking groups selected fromtert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)—SO₂NRR; R¹⁰⁹ is heteroaryl of from 2 to 10 carbon atoms and 1 to 4heteroatoms selected from oxygen, nitrogen and sulfur within the ring oroxides thereof, having a single ring or multiple condensed rings; R¹¹⁰is substituted heteroaryl of from 2 to 10 carbon atoms and 1 to 4heteroatoms selected from oxygen, nitrogen and sulfur, substituted withfrom 1 to 3 substituents selected from the group consisting of (1) R²⁰¹;(2) unsymmetric di-substituted amines having different substituentsselected from the group consisting of R¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹,R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (3) amino groups blocked by blocking groupsselected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) andformyl; and (4) —SO₂NRR; R¹¹¹ is alkenyl of from 2 to 10 carbon atomsand from 1 to 2 sites of alkenyl unsaturation; R¹¹² is substitutedalkenyl, wherein substituted alkenyl is alkenyl substituted with from 1to 5 substituents selected from the group consisting of (1) R²⁰⁰; (2)unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of R¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵and R¹⁰⁶; (3) amino groups blocked by blocking groups selected fromtert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)R³⁰⁰; R¹¹³ is alkynyl of from 2 to 10 carbon atoms and from 1 to 2 sitesof alkynyl unsaturation; R¹¹⁴ is substituted alkynyl, whereinsubstituted alkynyl is alkynyl substituted with from 1 to 5 substituentsselected from the group consisting of (1) R²⁰⁰; (2) unsymmetricdi-substituted amines having different substituents selected from thegroup consisting of R¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶;(3) amino groups blocked by blocking groups selected fromtert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)R³⁰⁰; R¹¹⁵ is cycloalkenyl, wherein cycloalkenyl is a cyclic alkenylgroup of from 3 to 8 carbon atoms having single or multipleunsaturation, and which is not aromatic; R¹¹⁶ is substitutedcycloalkenyl of from 3 to 8 carbon atoms, having from 1 to 5substituents selected from the group consisting of (1) R²⁰⁰; (2) oxo(═O); (3) thioxo (═S); and (4) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (5) amino groups blocked byblocking groups sleeted from tert-butyloxycarbonyl (Boc), carbobenzyloxy(Cbz) and formyl; and (6) R³⁰⁰; wherein R²⁰⁰ is a member selected from(1) alkoxy; (2) substituted alkoxy; (3) acyl; (4) acylamino; (5)thiocarbonylamino; (6) acyloxy; (7) amino; (8) amidino; (9) alkylamidinowherein alkyl is R¹⁰¹; (10) thioamidino; (11) aminoacyl; (12)aminocarbonylamino; (13) aminothiocarbonylamino; (14) aminocarbonyloxy;(15) R¹⁰⁷; (16) R¹⁰⁸; (17) aryloxy; (18) substituted aryloxy; (19)aryloxyaryl; (20) substituted aryloxyaryl; (21) halogen; (22) hydroxyl;(23) cyano; (24) nitro; (25) carboxyl; (26) carboxylalkyl wherein alkylis R¹⁰¹; (27) carboxyl-substituted alkyl wherein substituted alkyl isR¹⁰²; (28) carboxyl-cycloalkyl wherein cycloalkyl is R¹⁰³; (29)carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R¹⁰⁴;(30) carboxylaryl wherein aryl is R¹⁰⁷; (31) carboxyl-substituted arylwherein substituted aryl is R¹⁰⁸; (32) carboxylheteroaryl whereinheteroaryl is R¹⁰⁹; (33) carboxyl-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (34) carboxylheterocyclic whereinheterocyclic is R¹⁰⁵; (35) carboxyl-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (36) R¹⁰³; (37) R¹⁰⁴; (38) guanidino;(39) guanidinosulfone; (40) thiol having the formula —SH; (41)thioalkyl; (42) substituted thioalkyl; (43) thioaryl; (44) substitutedthioaryl; (45) thiocycloalkyl; (46) substituted thiocycloalkyl; (47)thioheteroaryl; (48) substituted thioheteroaryl; (49) thioheterocyclic;(50) substituted thioheterocyclic; (51) R¹⁰⁹; (52) R¹¹⁰; (53) R¹⁰⁵; (54)R¹⁰⁶; (55) cycloalkoxy; (56) substituted cycloalkoxy; (57)heteroaryloxy; (58) substituted heteroaryloxy; (59) heterocyclyloxy;(60) substituted heterocyclyloxy; (61) oxycarbonylamino; (62)oxythiocarbonylamino; (63) —OS(O)₂-alkyl, wherein alkyl is R¹⁰¹; (64)—OS(O)₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (65)—OS(O)₂-aryl, wherein aryl is R¹⁰⁷; (66) —OS(O)₂-substituted arylwherein substituted aryl is R¹⁰⁸; (67) —OS(O)₂-heteroaryl whereinheteroaryl is R¹⁰⁹; (68) —OS(O)₂-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (69) —OS(O)₂-heterocyclic whereinheterocyclic is R¹⁰⁵; (70) —OS(O)₂-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (71) —OSO₂—NRR where R is hydrogen orR¹⁰¹; (72) —NRS(O)₂-alkyl, wherein alkyl is R¹⁰²; (73)—NRS(O)₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (74)—NRS(O)₂-aryl, wherein aryl is R¹⁰⁷; (75) —NRS(O)₂-substituted arylwherein substituted aryl is R¹⁰⁸; (76) —NRS(O)₂-heteroaryl whereinheteroaryl is R¹⁰⁹; (77) —NRS(O)₂-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (78) —NRS(O)₂-heterocyclic whereinheterocyclic is R¹⁰⁵; (79) —NRS(O)₂-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (80) —NRS(O)₂—NR-alkyl, wherein alkylis R¹⁰¹; (81) —NRS(O)₂—NR-substituted alkyl wherein substituted alkyl isR¹⁰²; (82) —NRS(O)₂—NR-aryl, wherein aryl is R¹⁰⁷; (83)—NRS(O)₂—NR-substituted aryl wherein substituted aryl is R¹⁰⁸; (84)—NRS(O)₂—NR-heteroaryl wherein heteroaryl is R¹⁰⁹; (85)—NRS(O)₂—NR-substituted heteroaryl wherein substituted heteroaryl isR¹¹⁰; (86) —NRS(O)₂—NR-heterocyclic wherein heterocyclic is R¹⁰⁵; (87)—NRS(O)₂—NR-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶, (88) mono- and di-alkylamino, wherein alkyl is R¹⁰¹; (89) mono-and di-(substituted alkyl)amino, wherein substituted alkyl is R¹⁰²; (90)mono- and di-arylamino wherein aryl is R¹⁰⁷; (91) mono- anddi-substituted arylamino wherein substituted aryl is R¹⁰⁸; (92) mono-and di-heteroarylamino wherein heteroaryl is R¹⁰⁹; (93) mono- anddi-substituted heteroarylamino wherein substituted heteroaryl is R¹¹⁰;(94) mono- and di-heterocyclic amino wherein heterocyclic is R¹⁰⁵; and(95) mono- and di-substituted heterocyclic amino wherein substitutedheterocyclic is R¹⁰⁶; R²⁰¹ is a member selected from (1) hydroxyl; (2)acyl; (3) acylamino; (4) thiocarbonylamino; (5) acyloxy; (6) R¹⁰¹; (7)R¹⁰²; (8) alkoxy; (9) substituted alkoxy; (10) R¹¹¹; (111) R¹¹²; (12)R¹¹³; (13) R¹¹⁴; (14) amidino; (15) alkylamidino, wherein alkyl is R¹⁰¹;(16) thioamidino; (17) amino; (18) aminoacyl; (19) aminocarbonyloxy;(20) aminocarbonylamino; (21) aminothiocarbonylamino; (22) R¹⁰⁷; (23)R¹⁰⁸; (24) aryloxy; (25) substituted aryloxy; (26) cycloalkoxy; (27)substituted cycloalkoxy; (28) heteroaryloxy; (29) substitutedheteroaryloxy; (30) heterocyclyloxy; (31) substituted heterocyclyloxy;(32) carboxyl; (33) carboxylalkyl wherein alkyl is R¹⁰¹; (34)carboxyl-substituted alkyl wherein substituted alkyl is R¹⁰²; (35)carboxyl-cycloalkyl wherein cycloalkyl is R¹⁰³; (36)carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R¹⁰⁴;(37) carboxylaryl wherein aryl is R¹⁰⁷; (38) carboxyl-substituted arylwherein substituted aryl is R¹⁰⁸; (39) carboxylheteroaryl whereinheteroaryl is R¹⁰⁹; (40) carboxyl-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (41) carboxylheterocyclic whereinheterocyclic is R¹⁰⁵; (42) carboxyl-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (43) carboxylamido; (44) cyano; (45)thiol having the formula —SH; (46) thioalkyl; (47) substitutedthioalkyl; (48) thioaryl; (49) substituted thioaryl (50) thioheteroaryl;(51) substituted thioheteroaryl; (52) thiocycloalkyl; (53) substitutedthiocycloalkyl; (54) thioheterocyclic; (55) substitutedthioheterocyclic; (56) R¹⁰³; (57) R¹⁰⁴; (58) guanidino; (59)guanidinosulfone; (60) halogen; (61) nitro; (62) R¹⁰⁹; (63) R¹¹⁰; (64)R^(10′); (65) R¹⁰⁶; (66) cycloalkoxy; (67) substituted cycloalkoxy; (68)heteroaryloxy; (69) substituted heteroaryloxy; (70) heterocyclyloxy;(71) substituted heterocyclyloxy; (72) oxycarbonylamino; (73)oxythiocarbonylamino; (74) —S(O)₂-alkyl wherein alkyl is R¹⁰¹; (75)—S(O)₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (76)—S(O)₂-cycloalkyl wherein cycloalkyl is R¹⁰³; (77) —S(O)₂-substitutedcycloalkyl wherein substituted cycloalkyl is R¹⁰⁴; (78) —S(O)₂-alkenylwherein alkenyl is R¹¹¹; (79) —S(O)₂-substituted alkenyl whereinsubstituted alkenyl is R¹¹²; (80) —S(O)₂-aryl wherein aryl is R¹⁰⁷; (81)—S(O)₂-substituted aryl wherein substituted aryl is R¹⁰⁸; (82)—S(O)₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (83) —S(O)₂-substitutedheteroaryl wherein substituted heteroaryl is R¹¹⁰; (84)—S(O)₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (85)—S(O)₂-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶; (86) —OS(O)₂-alkyl wherein alkyl is R¹⁰¹; (87) —OS(O)₂-substitutedalkyl wherein substituted alkyl is R¹⁰²; (88) —OS(O)₂-aryl wherein arylis R¹⁰⁷; (89) —OS(O)₂-substituted aryl wherein substituted aryl is R¹⁰⁸;(90) —OS(O)₂-heteroaryl wherein heteroaryl is 8109; (91)—OS(O)₂-substituted heteroaryl wherein substituted heteroaryl is R¹¹⁰;(92) —OS(O)₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (93)—OS(O)₂-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶; (94) —OSO₂—NRR where R is hydrogen or R¹⁰¹; (95) —NRS(O)₂-alkylwherein alkyl is R¹⁰¹; (96) —NRS(O)₂-substituted alkyl whereinsubstituted alkyl is R¹⁰²; (97) —NRS(O)₂-aryl wherein aryl is R¹⁰⁷; (98)—NRS(O)₂-substituted aryl wherein substituted aryl is R¹⁰⁸; (99)—NRS(O)₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (100)—NRS(O)₂-substituted heteroaryl wherein substituted heteroaryl is R¹¹⁰;(101) —NRS(O)₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (102)—NRS(O)₂-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶; (103) —NRS(O)₂—NR-alkyl wherein alkyl is R¹⁰¹; (104)—NRS(O)₂—NR-substituted alkyl wherein substituted alkyl is R¹⁰²; (105)—NRS(O)₂—NR-aryl wherein aryl is R¹⁰⁷; (106) —NRS(O)₂—NR-substitutedaryl wherein substituted aryl is R¹⁰⁸; (107) —NRS(O)₂—NR-heteroarylwherein heteroaryl is R¹⁰⁹; (108) —NRS(O)₂—NR-substituted heteroarylwherein substituted heteroaryl is R¹¹⁰; (109) —NRS(O)₂—NR-heterocyclicwherein heterocyclic is R¹⁰⁵; (110) —NRS(O)₂—NR-substituted heterocyclicwherein substituted heterocyclic is R¹⁰⁶, (111) mono- and di-alkylamino,wherein alkyl is R¹⁰¹; (112) mono- and di-(substituted alkyl)amino,wherein substituted alkyl is R¹⁰²; (113) mono- and di-arylamino whereinaryl is R¹⁰⁷; (114) mono- and di-substituted arylamino whereinsubstituted aryl is R¹⁰⁸; (115) mono- and di-heteroarylamino whereinheteroaryl is R¹⁰⁹; (116) mono- and di-substituted heteroarylaminowherein substituted heteroaryl is R¹¹⁰; (117) mono- and di-heterocyclicamino wherein heterocyclic is R¹⁰⁵; (118) mono- and di-substitutedheterocyclic amino wherein substituted heterocyclic is R¹⁰⁶; R³⁰⁰ is amember selected from (i) —SO₂-alkyl wherein alkyl is R¹⁰¹; (ii)—SO₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (iii)—SO₂-alkenyl wherein alkenyl is R¹¹¹; (iv) —SO₂-substituted alkenylwherein substituted alkenyl is R¹¹²; (v) —SO₂-cycloalkyl whereincycloalkyl is R¹⁰³; (vi) —SO₂-substituted cycloalkyl wherein substitutedcycloalkyl is R¹⁰⁴; (vii) —SO₂-aryl wherein aryl is R¹⁰⁷; (viii)—SO₂-substituted aryl wherein substituted aryl is R¹⁰⁸; (ix)—SO₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (x) —SO₂-substitutedheteroaryl wherein substituted heteroaryl is R¹¹⁰; (xi)—SO₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (xii) —SO₂-substitutedheterocyclic wherein substituted heterocyclic is R¹⁰⁶; and (xiii)—SO₂NRR; alkoxy has the formula “alkyl-O—”, wherein alkyl is R¹⁰¹;substituted alkoxy has the formula “substituted alkyl-O—”, whereinsubstituted alkyl is R¹⁰²; cycloalkoxy has the formula “—O-cycloalkyl”,wherein cycloalkyl is R¹⁰³; substituted cycloalkoxy has the formula“—O-substituted cycloalkyl”, wherein substituted cycloalkyl is R¹⁰⁴;alkenoxy has the formula “alkenyl-O—”, wherein alkenyl is R¹¹¹;substituted alkenoxy has the formula “substituted alkenyl-O—”, whereinsubstituted alkenyl is R¹¹²; cycloalkenoxy has the formula“cycloalkenyl-O—”, wherein cycloalkenyl is R¹¹⁵; substitutedcycloalkenoxy has the formula “substituted cycloalkenyl-O—”, whereinsubstituted cycloalkenyl is R¹¹⁶; aryloxy has the formula “aryl-O—”,wherein aryl is R¹⁰⁷; substituted aryloxy has the formula “substitutedaryl-O—”, wherein substituted aryl is R¹⁰⁸; heteroaryloxy has theformula “—O-heteroaryl”, wherein heteroaryl is R¹⁰⁹; substitutedheteroaryloxy has the formula “—O-substituted heteroaryl”, whereinsubstituted heteroaryl is R¹¹⁰; heterocyclyloxy has the formula“—O-heterocyclic”, wherein heterocyclic is R¹⁰⁵; substitutedheterocyclyloxy has the formula “—O-substituted heterocyclic”, whereinsubstituted heterocyclic is R¹⁰⁶; aryloxyaryl has the formula“aryl-O-aryl”, wherein each aryl is R¹⁰⁷; substituted aryloxyaryl hasthe formula “aryl-O-aryl”, wherein each aryl is R¹⁰⁷, substituted on oneor both aryl rings with from 1 to 3 substituents selected from the groupconsisting of (1) R²⁰¹; (2) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (3) amino groups blocked byblocking groups selected from tert-butyloxycarbonyl (Boc),carbobenzyloxy (Cbz) and formyl; and (4) —SO₂NRR; acyl is R^(c)—C(O)—;acylamino is selected from the group —C(O)NR^(c)R^(c), wherein eachR^(c) is optionally joined to form together with the nitrogen atom aheterocyclic or substituted heterocyclic ring, wherein heterocyclic isR¹⁰⁵ and substituted heterocyclic is R¹⁰⁶; thiocarbonylamino is selectedfrom the group —C(S)NR^(c)R^(c), wherein each R^(c) is optionally joinedto form together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring, wherein heterocyclic is R¹⁰⁵ and substitutedheterocyclic R¹⁰⁶; acyloxy is selected from R^(b)—C(O)O—; oxysulfonylhas the formula R^(b)—SO₂O—; amino has the formula —NH₂; substitutedamino has the formula NR^(d)R^(d), where each R^(d) is independentlyselected from the group consisting of hydrogen, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴,R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, R¹¹⁴ and—SO₂—R^(e), wherein R^(e) is a member selected from R¹⁰¹, R¹⁰², R¹⁰³,R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹ and R¹¹²; or the R^(d)groups can be joined together with the nitrogen atom to form aheterocyclic or a substituted heterocyclic ring, wherein heterocyclic isR¹⁰⁵ and substituted heterocyclic is R¹⁰⁶, provided that both R^(d)groups are not hydrogen; amidino has the formula H₂NC(═NH)—; alkylamidino is “alkylHNC(═NH)-”, wherein alkyl is R¹⁰¹; thioamidino has theformula RSC(═NH)—; aminoacyl has the formula —NRC(O)R^(b); aminosulfonylhaving the formula —NRSO₂R^(b); aminocarbonyloxy having the formula—NRC(O)O—R^(b); aminosulfonyloxy has the formula —NRSO₂O—R^(b);oxycarbonylamino has the formula —OC(O)NH₂, —OC(O)NRR or —OC(O)NRR^(b),wherein each R is optionally joined to form together with the nitrogenatom a heterocyclic or substituted heterocyclic ring, whereinheterocyclic is R¹⁰⁵ and substituted heterocyclic is R¹⁰⁶;oxythiocarbonylamino has the formula —OC(S)NH₂, —OC(S)NRR or—OC(S)NR^(b), wherein each R is optionally joined to form together withthe nitrogen atom a heterocyclic or substituted heterocyclic ring,wherein heterocyclic is R¹⁰⁵ and substituted heterocyclic is R¹⁰⁶;aminocarbonylamino has the formula NR^(f)C(O)NR^(f)R^(f) or—NR^(f)C(O)NR^(f)R^(b), wherein each R^(f) is optionally joined to formtogether with the nitrogen atom a heterocyclic or substitutedheterocyclic ring, wherein heterocyclic is R¹⁰⁵ and substitutedheterocyclic is R¹⁰⁶; aminothiocarbonylamino has the formula—NR^(f)C(S)NR^(f)R^(f) or —NR^(f)(S)NR^(f)R^(b), wherein each R^(f) isoptionally joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring, wherein heterocyclic is R¹⁰⁵ andsubstituted heterocyclic is R¹⁰⁶; aminosulfonylamino has the formulaNR^(f)SO₂NR^(f)R^(f) or —NR^(f)SO₂NR^(f)R^(b), wherein each R^(f) isoptionally joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring, wherein heterocyclic is R¹⁰⁵ andsubstituted heterocyclic is R¹⁰⁶; oxysulfonylamino has the formula—OSO₂NH₂, —OSO₂NRR or —OSO₂NRR^(b), wherein each R is optionally joinedto form together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring, wherein heterocyclic is R¹⁰⁵ and substitutedheterocyclic is R¹⁰⁶; halogen is fluoro, chloro, bromo or iodo;guanidino has the formula —NR^(f)C(═NR^(f)NR^(f)R^(f) or—NR^(f)C(═NR^(f)NR^(b); guanidinosulfone has the formula—NRC(═NR)NRSO₂—R^(b); thioalkyl having the formula “—S-alkyl”, whereinalkyl is R¹⁰¹; substituted thioalkyl has the formula “—S-substitutedalkyl”, wherein substituted alkyl is R¹⁰²; thiocycloalkyl has theformula “—S-cycloalkyl”, wherein cycloalkyl is R¹⁰³; substitutedthiocycloalkyl has the formula “—S-substituted cycloalkyl”, whereinsubstituted cycloalkyl is R¹⁰⁴; thioaryl has the formula “—S-aryl”,wherein aryl is R¹⁰⁷; substituted thioaryl has the formula“—S-substituted aryl”, wherein substituted aryl is R¹⁰⁸; thioheteroarylhas the formula “—S-heteroaryl”, wherein heteroaryl is R¹⁰⁹; substitutedthioheteroaryl has the formula “—S-substituted heteroaryl”, whereinsubstituted heteroaryl is R¹¹⁰; thioheterocyclic has the formula“—S-heterocyclic”, wherein heterocyclic is R¹⁰⁵; and substitutedthioheterocyclic has the formula “—S-substituted heterocyclic”, whereinsubstituted heterocyclic is R¹⁰⁶; wherein each R is independentlyhydrogen or R¹⁰¹; each R^(b) is a member independently selected fromR¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹²,R¹¹³ and R¹¹⁴; each R^(c) is a member independently selected from H,R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹²,R¹¹³ and R¹¹⁴; and each R^(f) is independently hydrogen, R¹⁰¹ or ablocking group selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy(Cbz) and formyl.
 76. The compound of claim 75, wherein ring A issubstituted with substituted amino.
 77. The compound of claim 76,wherein the substituted amino is dialkyl amino.
 78. The compound ofclaim 75, wherein R³ is —CH₂—Ar—R⁹, where Ar is R¹⁰⁷.
 79. The compoundof claim 75, wherein X is hydroxyl.
 80. The compound of claim 75, havingthe formula:

or a pharmaceutically acceptable salt or ester thereof, wherein ring Aforms a pyrazine ring substituted with substituted amino; and x is aninteger from 1 to
 4. 81. The compound of claim 80, wherein thesubstituted amino on ring A is disubstituted with alkyl.
 82. Thecompound of claim 75 having a structure according to Formula B:

or a pharmaceutically acceptable salt thereof, wherein R¹¹ and R^(11′)are independently selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹¹⁵ and R¹¹⁶, or R¹¹ and R^(11′) are joined toform a heterocyclic or a substituted heterocyclic ring, whereinheterocyclic is R¹⁰⁵ and substituted heterocyclic is R¹⁰⁶; and R¹⁶ andR¹⁷ are independently selected from the group consisting of hydrogen,R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, alkoxy,substituted alkoxy, amino, and substituted amino, wherein R¹⁰¹, R¹⁰²,R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹⁵ and R¹¹⁶ aredefined as in claim
 1. 83. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R⁵ is selectedfrom the group consisting of R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷,R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹², R¹¹⁵ and R¹¹⁶; R⁶ is selected from thegroup consisting of hydrogen, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷,R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹⁵ and R¹¹⁶; R′ and R″ are independently selectedfrom the group consisting of hydrogen and R¹⁰¹, or R′ and R″, togetherwith the nitrogen to which they are bound, join to form a heterocyclicgroup, wherein heterocyclic is R¹⁰⁵; X is selected from the groupconsisting of hydroxyl, alkoxy and substituted alkoxy; and R^(9′) isselected from the group consisting of hydrogen, acylamino, aminoacyl,oxycarbonylamino, aminocarbonyloxy and R¹⁰⁵, wherein R¹⁰¹ is alkyl offrom 1 to 10 carbon atoms; R¹⁰² is substituted alkyl of from 1 to 10carbon atoms, having from 1 to 5 substituents selected from the groupconsisting of (1) R²⁰⁰; (2) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (3) amino groups blocked byblocking groups selected from the group consisting oftert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)R³⁰⁰; R¹⁰³ is cycloalkyl of from 3 to 8 carbon atoms; R¹⁰⁴ issubstituted cycloalkyl of from 3 to 8 carbon atoms, having from 1 to 5substituents selected from the group consisting of (1) R²⁰⁰; (2) oxo(═O); (3) thioxo (═S); (4) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (5) amino groups blocked byblocking groups selected from tert-butyloxycarbonyl (Boc),carbobenzyloxy (Cbz) and formyl; and (6) R³⁰⁰; R¹⁰⁵ is heterocyclicreferring to a saturated or unsaturated group having from 1 to 10 carbonatoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur andoxygen, and having a single ring or multiple fused rings, wherein infused ring systems one or more of the rings can be aryl (R¹⁰⁷) orheteroaryl (R¹⁰⁹); R¹⁰⁶ is substituted heterocyclic of from 1 to 10carbon atoms and from 1 to 4 heteroatoms, substituted with from 1 to 3substituents selected from the group consisting of (1) R²⁰⁰; (2) oxo(═O); (3) thioxo (═S); (4) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (5) amino groups blocked byblocking groups selected from tert-butyloxycarbonyl (Boc),carbobenzyloxy (Cbz) and formyl; and (6) R³⁰⁰; R¹⁰⁷ is aryl, whereinaryl is an unsaturated aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring or multiple condensed rings, wherein thecondensed rings may or may not be aromatic; R¹⁰⁸ is substituted aryl,wherein substituted aryl is aryl substituted with from 1 to 3substituents selected from the group consisting of (1) R²⁰¹; (2)unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of R¹⁰¹, R¹⁰², R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹and R¹¹⁰; (3) amino groups blocked by blocking groups selected fromtert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)—SO₂NRR; R¹⁰⁹ is heteroaryl of from 2 to 10 carbon atoms and 1 to 4heteroatoms selected from oxygen, nitrogen and sulfur within the ring oroxides thereof, having a single ring or multiple condensed rings; R¹¹⁰is substituted heteroaryl of from 2 to 10 carbon atoms and 1 to 4heteroatoms selected from oxygen, nitrogen and sulfur, substituted withfrom 1 to 3 substituents selected from the group consisting of (1) R²⁰¹;(2) unsymmetric di-substituted amines having different substituentsselected from the group consisting of R¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹,R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (3) amino groups blocked by blocking groupsselected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) andformyl; and (4) —SO₂NRR; R¹¹¹ is alkenyl of from 2 to 10 carbon atomsand from 1 to 2 sites of alkenyl unsaturation; R¹¹² is substitutedalkenyl, wherein substituted alkenyl is alkenyl substituted with from 1to 5 substituents selected from the group consisting of (1) R²⁰⁰; (2)unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of R¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵and R¹⁰⁶; (3) amino groups blocked by blocking groups selected fromtert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)R³⁰⁰; R¹¹³ is alkynyl of from 2 to 10 carbon atoms and from 1 to 2 sitesof alkynyl unsaturation; R¹¹⁴ is substituted alkynyl, whereinsubstituted alkynyl is alkynyl substituted with from 1 to 5 substituentsselected from the group consisting of (1) R²⁰⁰; (2) unsymmetricdi-substituted amines having different substituents selected from thegroup consisting of R¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶;(3) amino groups blocked by blocking groups selected fromtert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)R³⁰⁰; R¹¹⁵ is cycloalkenyl, wherein cycloalkenyl is a cyclic alkenylgroup of from 3 to 8 carbon atoms having single or multipleunsaturation, and which is not aromatic; R¹¹⁶ is substitutedcycloalkenyl of from 3 to 8 carbon atoms, having from 1 to 5substituents selected from the group consisting of (1) R²⁰⁰; (2) oxo(═O); (3) thioxo (═S); and (4) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (5) amino groups blocked byblocking groups sleeted from tert-butyloxycarbonyl (Boc), carbobenzyloxy(Cbz) and formyl; and (6) R³⁰⁰; wherein R²⁰⁰ is a member selected from(1) alkoxy; (2) substituted alkoxy; (3) acyl; (4) acylamino; (5)thiocarbonylamino; (6) acyloxy; (7) amino; (8) amidino; (9) alkylamidinowherein alkyl is R¹⁰¹; (10) thioamidino; (11) aminoacyl; (12)aminocarbonylamino; (13) aminothiocarbonylamino; (14) aminocarbonyloxy;(15) R¹⁰⁷; (16) R¹⁰⁸; (17) aryloxy; (18) substituted aryloxy; (19)aryloxyaryl; (20) substituted aryloxyaryl; (21) halogen; (22) hydroxyl;(23) cyano; (24) nitro; (25) carboxyl; (26) carboxylalkyl wherein alkylis R¹⁰¹; (27) carboxyl-substituted alkyl wherein substituted alkyl isR¹⁰²; (28) carboxyl-cycloalkyl wherein cycloalkyl is R¹⁰³; (29)carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R¹⁰⁴;(30) carboxylaryl wherein aryl is R¹⁰⁷; (31) carboxyl-substituted arylwherein substituted aryl is R¹⁰⁸; (32) carboxylheteroaryl whereinheteroaryl is R¹⁰⁹; (33) carboxyl-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (34) carboxylheterocyclic whereinheterocyclic is R¹⁰⁵; (35) carboxyl-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (36) R¹⁰³; (37) R¹⁰⁴; (38) guanidino;(39) guanidinosulfone; (40) thiol having the formula —SH; (41)thioalkyl; (42) substituted thioalkyl; (43) thioaryl; (44) substitutedthioaryl; (45) thiocycloalkyl; (46) substituted thiocycloalkyl; (47)thioheteroaryl; (48) substituted thioheteroaryl; (49) thioheterocyclic;(50) substituted thioheterocyclic; (51) R¹⁰⁹; (52) R¹¹⁰; (53) R¹⁰⁵; (54)R¹⁰⁶; (55) cycloalkoxy; (56) substituted cycloalkoxy; (57)heteroaryloxy; (58) substituted heteroaryloxy; (59) heterocyclyloxy;(60) substituted heterocyclyloxy; (61) oxycarbonylamino; (62)oxythiocarbonylamino; (63) —OS(O)₂-alkyl, wherein alkyl is R¹⁰¹; (64)—OS(O)₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (65)—OS(O)₂-aryl, wherein aryl is R¹⁰⁷; (66) —OS(O)₂-substituted arylwherein substituted aryl is R¹⁰⁸; (67) —OS(O)₂-heteroaryl whereinheteroaryl is R¹⁰⁹; (68) —OS(O)₂-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (69) —OS(O)₂-heterocyclic whereinheterocyclic is R¹⁰⁵; (70) —OS(O)₂-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (71) —OSO₂—NRR where R is hydrogen orR¹⁰¹; (72) —NRS(O)₂-alkyl, wherein alkyl is R¹⁰¹; (73)—NRS(O)₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (74)—NRS(O)₂-aryl, wherein aryl is R¹⁰⁷; (75) —NRS(O)₂-substituted arylwherein substituted aryl is R¹⁰⁸; (76) —NRS(O)₂-heteroaryl whereinheteroaryl is R¹⁰⁹; (77) —NRS(O)₂-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (78) —NRS(O)₂-heterocyclic whereinheterocyclic is R¹⁰⁵; (79) —NRS(O)₂-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (80) —NRS(O)₂—NR-alkyl, wherein alkylis R¹⁰¹; (81) —NRS(O)₂—NR-substituted alkyl wherein substituted alkyl isR¹⁰²; (82) —NRS(O)₂—NR-aryl, wherein aryl is R¹⁰⁷; (83)—NRS(O)₂—NR-substituted aryl wherein substituted aryl is R¹⁰⁸; (84)—NRS(O)₂—NR-heteroaryl wherein heteroaryl is R¹⁰⁹; (85)—NRS(O)₂—NR-substituted heteroaryl wherein substituted heteroaryl isR¹¹⁰; (86) —NRS(O)₂—NR-heterocyclic wherein heterocyclic is R¹⁰⁵; (87)—NRS(O)₂—NR-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶, (88) mono- and di-alkylamino, wherein alkyl is R¹⁰¹; (89) mono-and di-(substituted alkyl)amino, wherein substituted alkyl is R¹⁰²; (90)mono- and di-arylamino wherein aryl is R¹⁰⁷; (91) mono- anddi-substituted arylamino wherein substituted aryl is R¹⁰⁸; (92) mono-and di-heteroarylamino wherein heteroaryl is R¹⁰⁹; (93) mono- anddi-substituted heteroarylamino wherein substituted heteroaryl is R¹¹⁰;(94) mono- and di-heterocyclic amino wherein heterocyclic is R¹⁰⁵; and(95) mono- and di-substituted heterocyclic amino wherein substitutedheterocyclic is R¹⁰⁶; R²⁰¹ is a member selected from (1) hydroxyl; (2)acyl; (3) acylamino; (4) thiocarbonylamino; (5) acyloxy; (6) R¹⁰¹; (7)R¹⁰²; 8) alkoxy; (9) substituted alkoxy; (10) R¹¹¹; (11) R¹¹²; (12)R¹¹³; (13) R¹¹⁴; (14) amidino; (15) alkylamidino, wherein alkyl is R¹⁰¹;(16) thioamidino; (17) amino; (18) aminoacyl; (19) aminocarbonyloxy;(20) aminocarbonylamino; (21) aminothiocarbonylamino; (22) R¹⁰⁷; (23)R¹⁰⁸; (24) aryloxy; (25) substituted aryloxy; (26) cycloalkoxy; (27)substituted cycloalkoxy; (28) heteroaryloxy; (29) substitutedheteroaryloxy; (30) heterocyclyloxy; (31) substituted heterocyclyloxy;(32) carboxyl; (33) carboxylalkyl wherein alkyl is R¹⁰¹; (34)carboxyl-substituted alkyl wherein substituted alkyl is R¹⁰²; (35)carboxyl-cycloalkyl wherein cycloalkyl is R¹⁰³; (36)carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R¹⁰⁴;(37) carboxylaryl wherein aryl is R¹⁰⁷; (38) carboxyl-substituted arylwherein substituted aryl is R¹⁰⁸; (39) carboxylheteroaryl whereinheteroaryl is R¹⁰⁹; (40) carboxyl-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (41) carboxylheterocyclic whereinheterocyclic is R¹⁰⁵; (42) carboxyl-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (43) carboxylamido; (44) cyano; (45)thiol having the formula —SH; (46) thioalkyl; (47) substitutedthioalkyl; (48) thioaryl; (49) substituted thioaryl (50) thioheteroaryl;(51) substituted thioheteroaryl; (52) thiocycloalkyl; (53) substitutedthiocycloalkyl; (54) thioheterocyclic; (55) substitutedthioheterocyclic; (56) R¹⁰³; (57) R¹⁰⁴; (58) guanidino; (59)guanidinosulfone; (60) halogen; (61) nitro; (62) R¹⁰⁹; (63) R¹¹⁰; (64)R¹⁰⁵; (65) R¹⁰⁶; (66) cycloalkoxy; (67) substituted cycloalkoxy; (68)heteroaryloxy; (69) substituted heteroaryloxy; (70) heterocyclyloxy;(71) substituted heterocyclyloxy; (72) oxycarbonylamino; (73)oxythiocarbonylamino; (74) —S(O)₂-alkyl wherein alkyl is R¹⁰¹; (75)—S(O)₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (76)—S(O)₂-cycloalkyl wherein cycloalkyl is R¹⁰³; (77) —S(O)₂-substitutedcycloalkyl wherein substituted cycloalkyl is R¹⁰⁴; (78) —S(O)₂-alkenylwherein alkenyl is R¹¹¹; (79) —S(O)₂-substituted alkenyl whereinsubstituted alkenyl is R¹¹²; (80) —S(O)₂-aryl wherein aryl is R¹⁰⁷; (81)—S(O)₂-substituted aryl wherein substituted aryl is R¹⁰⁸; (82)—S(O)₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (83) —S(O)₂-substitutedheteroaryl wherein substituted heteroaryl is R¹¹⁰; (84)—S(O)₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (85)—S(O)₂-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶; (86) —OS(O)₂-alkyl wherein alkyl is R¹⁰¹; (87) —OS(O)₂-substitutedalkyl wherein substituted alkyl is R¹⁰²; (88) —OS(O)₂-aryl wherein arylis R¹⁰⁷; (89) —OS(O)₂-substituted aryl wherein substituted aryl is R¹⁰⁸;(90) —OS(O)₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (91)—OS(O)₂-substituted heteroaryl wherein substituted heteroaryl is R¹¹⁰;(92) —OS(O)₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (93)—OS(O)₂-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶; (94) —OSO₂—NRR where R is hydrogen or R¹⁰¹; (95) —NRS(O)₂-alkylwherein alkyl is R¹⁰¹; (96) —NRS(O)₂-substituted alkyl whereinsubstituted alkyl is R¹⁰²; (97) —NRS(O)₂-aryl wherein aryl is R¹⁰⁷; (98)—NRS(O)₂-substituted aryl wherein substituted aryl is R¹⁰⁸; (99)—NRS(O)₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (100)—NRS(O)₂-substituted heteroaryl wherein substituted heteroaryl is R¹¹⁰;(101) —NRS(O)₂-heterocyclic wherein heterocyclic is R¹⁰³; (102)—NRS(O)₂-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶; (103) —NRS(O)₂—NR-alkyl wherein alkyl is R¹⁰¹; (104)—NRS(O)₂—NR-substituted alkyl wherein substituted alkyl is R¹⁰²; (105)—NRS(O)₂—NR-aryl wherein aryl is R¹⁰⁷; (106) —NRS(O)₂—NR-substitutedaryl wherein substituted aryl is R¹⁰⁸; (107) —NRS(O)₂—NR-heteroarylwherein heteroaryl is R¹⁰⁹; (108) —NRS(O)₂—NR-substituted heteroarylwherein substituted heteroaryl is R¹¹⁰; (109) —NRS(O)₂—NR-heterocyclicwherein heterocyclic is R¹⁰⁵; (110) —NRS(O)₂—NR-substituted heterocyclicwherein substituted heterocyclic is R¹⁰⁶, (111) mono- and di-alkylamino,wherein alkyl is R¹⁰¹; (112) mono- and di-(substituted alkyl)amino,wherein substituted alkyl is R¹⁰²; (113) mono- and di-arylamino whereinaryl is R¹⁰⁷; (114) mono- and di-substituted arylamino whereinsubstituted aryl is R¹⁰⁸; (115) mono- and di-heteroarylamino whereinheteroaryl is R¹⁰⁹; (116) mono- and di-substituted heteroarylaminowherein substituted heteroaryl is R¹¹⁰; (117) mono- and di-heterocyclicamino wherein heterocyclic is R¹⁰⁵; (118) mono- and di-substitutedheterocyclic amino wherein substituted heterocyclic is R¹⁰⁶; R³⁰⁰ is amember selected from (i) —SO₂-alkyl wherein alkyl is R¹⁰¹; (ii)—SO₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (iii)—SO₂-alkenyl wherein alkenyl is R¹¹¹; (iv) —SO₂-substituted alkenylwherein substituted alkenyl is R¹¹²; (v) —SO₂-cycloalkyl whereincycloalkyl is R¹⁰³; (vi) —SO₂-substituted cycloalkyl wherein substitutedcycloalkyl is R¹⁰⁴; (vii) —SO₂-aryl wherein aryl is R¹⁰⁷; (viii)—SO₂-substituted aryl wherein substituted aryl is R¹⁰⁸; (ix)—SO₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (x) —SO₂-substitutedheteroaryl wherein substituted heteroaryl is R¹¹⁰; (xi)—SO₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (xii) —SO₂-substitutedheterocyclic wherein substituted heterocyclic is R¹⁰⁶; and (xiii)—SO₂NRR; alkoxy has the formula “alkyl-O—”, wherein alkyl is R¹⁰¹;substituted alkoxy has the formula “substituted alkyl-O—”, whereinsubstituted alkyl is R¹⁰²; cycloalkoxy has the formula “—O-cycloalkyl”,wherein cycloalkyl is R¹⁰³; substituted cycloalkoxy has the formula“—O-substituted cycloalkyl”, wherein substituted cycloalkyl is R¹⁰⁴;alkenoxy has the formula “alkenyl-O—”, wherein alkenyl is R¹¹¹;substituted alkenoxy has the formula “substituted alkenyl-O—”, whereinsubstituted alkenyl is R¹¹²; cycloalkenoxy has the formula“cycloalkenyl-O—”, wherein cycloalkenyl is R¹¹⁵; substitutedcycloalkenoxy has the formula “substituted cycloalkenyl-O—”, whereinsubstituted cycloalkenyl is R¹¹⁶; aryloxy has the formula “aryl-O—”,wherein aryl is R¹⁰⁷; substituted aryloxy has the formula “substitutedaryl-O—”, wherein substituted aryl is R¹⁰⁸; heteroaryloxy has theformula “—O-heteroaryl”, wherein heteroaryl is R¹⁰⁹; substitutedheteroaryloxy has the formula “—O-substituted heteroaryl”, whereinsubstituted heteroaryl is R¹¹⁰; heterocyclyloxy has the formula“—O-heterocyclic”, wherein heterocyclic is R¹⁰⁵; substitutedheterocyclyloxy has the formula “—O-substituted heterocyclic”, whereinsubstituted heterocyclic is R¹⁰⁶; aryloxyaryl has the formula“aryl-O-aryl”, wherein each aryl is R¹⁰⁷; substituted aryloxyaryl hasthe formula “aryl-O-aryl”, wherein each aryl is R¹⁰⁷, substituted on oneor both aryl rings with from 1 to 3 substituents selected from the groupconsisting of (1) R²⁰¹; (2) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (3) amino groups blocked byblocking groups selected from tert-butyloxycarbonyl (Boc),carbobenzyloxy (Cbz) and formyl; and (4) —SO₂NRR; acyl is R^(c)—C(O)—;acylamino is selected from the group —C(O)NR^(c)R^(c), wherein eachR^(c) is optionally joined to form together with the nitrogen atom aheterocyclic or substituted heterocyclic ring, wherein heterocyclic isR¹⁰⁵ and substituted heterocyclic is R¹⁰⁶; thiocarbonylamino is selectedfrom the group —C(S)NR^(c)R^(c), wherein each R^(c) is optionally joinedto form together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring, wherein heterocyclic is R¹⁰⁵ and substitutedheterocyclic R¹⁰⁶; acyloxy is selected from R^(b)—C(O)O—; oxysulfonylhas the formula R^(b)—SO₂O—; amino has the formula —NH₂; substitutedamino has the formula —NR^(d)R^(d), where each R^(d) is independentlyselected from the group consisting of hydrogen, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴,R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, R¹¹⁴ and—SO₂—R^(e), wherein R^(e) is a member selected from R¹⁰¹, R¹⁰², R¹⁰³,R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹ and R¹¹²; or the R^(d)groups can be joined together with the nitrogen atom to form aheterocyclic or a substituted heterocyclic ring, wherein heterocyclic isR¹⁰⁵ and substituted heterocyclic is R¹⁰⁶, provided that both R^(d)groups are not hydrogen; amidino has the formula H₂NC(═NH)—; alkylamidino is “alkylHNC(═NH)—”, wherein alkyl is R¹⁰¹; thioamidino has theformula RSC(═NH)—; aminoacyl has the formula —NRC(O)R^(b); aminosulfonylhaving the formula —NRSO₂R^(b); aminocarbonyloxy having the formula—NRC(O)O—R^(b); aminosulfonyloxy has the formula —NRSO₂O—R^(b);oxycarbonylamino has the formula —OC(O)NH₂, —OC(O)NRR or —OC(O)NRR^(b)wherein each R is optionally joined to form together with the nitrogenatom a heterocyclic or substituted heterocyclic ring, whereinheterocyclic is R¹⁰⁵ and substituted heterocyclic is R¹⁰⁶;oxythiocarbonylamino has the formula —OC(S)NH₂, —OC(S)NRR or—OC(S)NRR^(b), wherein each R is optionally joined to form together withthe nitrogen atom a heterocyclic or substituted heterocyclic ring,wherein heterocyclic is R¹⁰⁵ and substituted heterocyclic is R¹⁰⁶;aminocarbonylamino has the formula —NR^(f)C(O)NR^(f)R^(f) or—NR^(f)C(O)NR^(f)R^(b), wherein each R^(f) is optionally joined to formtogether with the nitrogen atom a heterocyclic or substitutedheterocyclic ring, wherein heterocyclic is R¹⁰⁵ and substitutedheterocyclic is R¹⁰⁶; aminothiocarbonylamino has the formulaNR^(f)C(S)NR^(f)R^(f) or —NR^(f)C(S)NR^(f)R^(b), wherein each isoptionally joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring, wherein heterocyclic is R¹⁰⁵ andsubstituted heterocyclic is R¹⁰⁶; aminosulfonylamino has the formula—NR^(f)SO₂NR^(f)R^(f) or —NR^(f)SO₂NR^(f)R^(b), wherein each R^(f) isoptionally joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring, wherein heterocyclic is R¹⁰⁵ andsubstituted heterocyclic is R¹⁰⁶; oxysulfonylamino has the formula—OSO₂NH₂, —OSO₂NRR or —OSO₂NRR^(b), wherein each R is optionally joinedto form together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring, wherein heterocyclic is R¹⁰⁵ and substitutedheterocyclic is R¹⁰⁶; halogen is fluoro, chloro, bromo or iodo;guanidino has the formula —NR^(f)C(═NR^(f))NR^(f)R^(f) or—NR^(f)C(═NR^(f))NR^(f)R^(b); guanidinosulfone has the formula—NRC(═NR)NRSO₂—R^(b); thioalkyl having the formula “—S-alkyl”, whereinalkyl is R¹⁰¹; substituted thioalkyl has the formula “—S-substitutedalkyl”, wherein substituted alkyl is R¹⁰²; thiocycloalkyl has theformula “—S-cycloalkyl”, wherein cycloalkyl is R¹⁰³; substitutedthiocycloalkyl has the formula “—S-substituted cycloalkyl”, whereinsubstituted cycloalkyl is R¹⁰⁴; thioaryl has the formula “—S-aryl”,wherein aryl is R¹⁰⁷; substituted thioaryl has the formula“—S-substituted aryl”, wherein substituted aryl is R¹⁰⁸; thioheteroarylhas the formula “—S-heteroaryl”, wherein heteroaryl is R¹⁰⁹; substitutedthioheteroaryl has the formula “—S-substituted heteroaryl”, whereinsubstituted heteroaryl is R¹¹⁰; thioheterocyclic has the formula“—S-heterocyclic”, wherein heterocyclic is R¹⁰⁵; and substitutedthioheterocyclic has the formula “—S-substituted heterocyclic”, whereinsubstituted heterocyclic is R¹⁰⁶; wherein each R is independentlyhydrogen or R¹⁰¹; each R^(b) is a member independently selected fromR¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹²,R¹¹³ and R¹¹⁴; each R^(f) is a member independently selected from H,R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹²,R¹¹³ and R¹¹⁴; and each R is independently hydrogen, R¹⁰¹ or a blockinggroup selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz)and formyl.
 84. A method for treating rheumatoid arthritis in a patient,which method comprises administering to the patient a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of formula IIa:

or a pharmaceutically acceptable salt thereof, wherein ring A forms apyrazine ring, optionally substituted with 1 or 2 substituents selectedfrom the group consisting of R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷,R¹⁰⁸, R¹⁰⁹, R¹¹⁰, alkoxy, substituted alkoxy, amino, substituted aminoand halogen, R³ is —(CH₂)_(x)—Ar—R⁹, wherein Ar is R¹⁰⁷ or R¹⁰⁹; X is aninteger from 0 to 4; and R⁹ is selected from the group consisting ofacyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, thioamidino,thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl,oxysulfonylamino and oxysulfonyl; R^(3′) is hydrogen; Q is —NR⁴—,wherein R⁴ is hydrogen or R¹⁰¹; R⁵ is selected from the group consistingof R¹⁰¹, R¹⁰², R¹⁰³, R₁₀₄, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹,R¹¹², R¹¹⁵ and R¹¹⁶; R⁶ is selected from the group consisting ofhydrogen, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰,R¹¹⁵ and R¹¹⁶; and X is selected from the group consisting of hydroxyl,alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy,substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy,aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy and —NR″R″, wherein each R″is independently selected from the group consisting of hydrogen, R¹⁰¹,R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹ and R¹¹²,wherein R¹⁰¹ is alkyl of from 1 to 10 carbon atoms; R¹⁰² is substitutedalkyl of from 1 to 10 carbon atoms, having from 1 to 5 substituentsselected from the group consisting of (1) R²⁰⁰; (2) unsymmetricdi-substituted amines having different substituents selected from thegroup consisting of R¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶;(3) amino groups blocked by blocking groups selected from the groupconsisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) andformyl; and (4) R³⁰⁰; R¹⁰³ is cycloalkyl of from 3 to 8 carbon atoms;R¹⁰⁴ is substituted cycloalkyl of from 3 to 8 carbon atoms, having from1 to 5 substituents selected from the group consisting of (1) R²⁰⁰; (2)oxo (═O); (3) thioxo (═S); (4) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (5) amino groups blocked byblocking groups selected from tert-butyloxycarbonyl (Boc),carbobenzyloxy (Cbz) and formyl; and (6) R³⁰⁰; R¹⁰⁵ is heterocyclicreferring to a saturated or unsaturated group having from 1 to 10 carbonatoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur andoxygen, and having a single ring or multiple fused rings, wherein infused ring systems one or more of the rings can be aryl (R¹⁰⁷) orheteroaryl (R¹⁰⁹); R¹⁰⁶ is substituted heterocyclic of from 1 to 10carbon atoms and from 1 to 4 heteroatoms, substituted with from 1 to 3substituents selected from the group consisting of (1) R²⁰⁰; (2) oxo(═O); (3) thioxo (═S); (4) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (5) amino groups blocked byblocking groups selected from tert-butyloxycarbonyl (Boc),carbobenzyloxy (Cbz) and formyl; and (6) R³⁰⁰; R¹⁰⁷ is aryl, whereinaryl is an unsaturated aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring or multiple condensed rings, wherein thecondensed rings may or may not be aromatic; R¹⁰⁸ is substituted aryl,wherein substituted aryl is aryl substituted with from 1 to 3substituents selected from the group consisting of (1) R²⁰¹; (2)unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of R¹⁰¹, R¹⁰², R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹and R¹¹⁰; (3) amino groups blocked by blocking groups selected fromtert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)—SO₂NRR; R¹⁰⁹ is heteroaryl of from 2 to 10 carbon atoms and 1 to 4heteroatoms selected from oxygen, nitrogen and sulfur within the ring oroxides thereof, having a single ring or multiple condensed rings; R¹¹⁰is substituted heteroaryl of from 2 to 10 carbon atoms and 1 to 4heteroatoms selected from oxygen, nitrogen and sulfur, substituted withfrom 1 to 3 substituents selected from the group consisting of (1) R²⁰¹;(2) unsymmetric di-substituted amines having different substituentsselected from the group consisting of R¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹,R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (3) amino groups blocked by blocking groupsselected from tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) andformyl; and (4) —SO₂NRR; R¹¹¹ is alkenyl of from 2 to 10 carbon atomsand from 1 to 2 sites of alkenyl unsaturation; R¹¹² is substitutedalkenyl, wherein substituted alkenyl is alkenyl substituted with from 1to 5 substituents selected from the group consisting of (1) R²⁰⁰; (2)unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of R¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵and R¹⁰⁶; (3) amino groups blocked by blocking groups selected fromtert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)R³⁰⁰; R¹¹³ is alkynyl of from 2 to 10 carbon atoms and from 1 to 2 sitesof alkynyl unsaturation; R¹¹⁴ is substituted alkynyl, whereinsubstituted alkynyl is alkynyl substituted with from 1 to 5 substituentsselected from the group consisting of (1) R²⁰⁰; (2) unsymmetricdi-substituted amines having different substituents selected from thegroup consisting of R¹⁰¹, R¹⁰², R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶;(3) amino groups blocked by blocking groups selected fromtert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz) and formyl; and (4)R³⁰⁰; R¹¹⁵ is cycloalkenyl, wherein cycloalkenyl is a cyclic alkenylgroup of from 3 to 8 carbon atoms having single or multipleunsaturation, and which is not aromatic; R¹¹⁶ is substitutedcycloalkenyl of from 3 to 8 carbon atoms, having from 1 to 5substituents selected from the group consisting of (1) R²⁰⁰; (2) oxo(═O); (3) thioxo (═S); and (4) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (5) amino groups blocked byblocking groups sleeted from tert-butyloxycarbonyl (Boc), carbobenzyloxy(Cbz) and formyl; and (6) R³⁰⁰. wherein R²⁰⁰ is a member selected from(1) alkoxy; (2) substituted alkoxy; (3) acyl; (4) acylamino; (5)thiocarbonylamino; (6) acyloxy; (7) amino; (8) amidino; (9) alkylamidinowherein alkyl is R¹⁰¹; (10) thioamidino; (11) aminoacyl; (12)aminocarbonylamino; (13) aminothiocarbonylamino; (14) aminocarbonyloxy;(15) R¹⁰⁷; (16) R¹⁰⁸; (17) aryloxy; (18) substituted aryloxy; (19)aryloxyaryl; (20) substituted aryloxyaryl; (21) halogen; (22) hydroxyl;(23) cyano; (24) nitro; (25) carboxyl; (26) carboxylalkyl wherein alkylis R¹⁰¹; (27) carboxyl-substituted alkyl wherein substituted alkyl isR¹⁰²; (28) carboxyl-cycloalkyl wherein cycloalkyl is R¹⁰³; (29)carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R¹⁰⁴;(30) carboxylaryl wherein aryl is R¹⁰⁷; (31) carboxyl-substituted arylwherein substituted aryl is R¹⁰⁸; (32) carboxylheteroaryl whereinheteroaryl is R¹⁰⁹; (33) carboxyl-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (34) carboxylheterocyclic whereinheterocyclic is R¹⁰⁵; (35) carboxyl-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (36) R¹⁰³; (37) R¹⁰⁴; (38) guanidino;(39) guanidinosulfone; (40) thiol having the formula —SH; (41)thioalkyl; (42) substituted thioalkyl; (43) thioaryl; (44) substitutedthioaryl; (45) thiocycloalkyl; (46) substituted thiocycloalkyl; (47)thioheteroaryl; (48) substituted thioheteroaryl; (49) thioheterocyclic;(50) substituted thioheterocyclic; (51) R¹⁰⁹; (52) R¹¹⁰; (53) R¹⁰⁵; (54)R¹⁰⁶; (55) cycloalkoxy; (56) substituted cycloalkoxy; (57)heteroaryloxy; (58) substituted heteroaryloxy; (59) heterocyclyloxy;(60) substituted heterocyclyloxy; (61) oxycarbonylamino; (62)oxythiocarbonylamino; (63) —OS(O)₂-alkyl, wherein alkyl is R¹⁰¹; (64)—OS(O)₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (65)—OS(O)₂-aryl, wherein aryl is R¹⁰⁷; (66) —OS(O)₂-substituted arylwherein substituted aryl is R¹⁰⁸; (67) —OS(O)₂-heteroaryl whereinheteroaryl is R¹⁰⁹; (68) —OS(O)₂-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (69) —OS(O)₂-heterocyclic whereinheterocyclic is R¹⁰⁵; (70) —OS(O)₂-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (71) —OSO₂—NRR where R is hydrogen orR¹⁰¹; (72) —NRS(O)₂-alkyl, wherein alkyl is R¹⁰¹; (73)—NRS(O)₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (74)—NRS(O)₂-aryl, wherein aryl is R¹⁰⁷; (75) —NRS(O)₂-substituted arylwherein substituted aryl is R¹⁰⁸; (76) —NRS(O)₂-heteroaryl whereinheteroaryl is R¹⁰⁹; (77) —NRS(O)₂-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (78) —NRS(O)₂-heterocyclic whereinheterocyclic is R¹⁰⁵; (79) —NRS(O)₂-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (80) —NRS(O)₂—NR-alkyl, wherein alkylis R¹⁰¹; (81) —NRS(O)₂—NR-substituted alkyl wherein substituted alkyl isR¹⁰²; (82) —NRS(O)₂—NR-aryl, wherein aryl is R¹⁰⁷; (83)—NRS(O)₂—NR-substituted aryl wherein substituted aryl is R¹⁰⁸; (84)—NRS(O)₂—NR-heteroaryl wherein heteroaryl is R¹⁰⁹; (85)—NRS(O)₂—NR-substituted heteroaryl wherein substituted heteroaryl isR¹¹⁰; (86) —NRS(O)₂—NR-heterocyclic wherein heterocyclic is R¹⁰⁵; (87)—NRS(O)₂—NR-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶, (88) mono- and di-alkylamino, wherein alkyl is R¹⁰¹; (89) mono-and di-(substituted alkyl)amino, wherein substituted alkyl is R¹⁰²; (90)mono- and di-arylamino wherein aryl is R¹⁰⁷; (91) mono- anddi-substituted arylamino wherein substituted aryl is R¹⁰⁸; (92) mono-and di-heteroarylamino wherein heteroaryl is R¹⁰⁹; (93) mono- anddi-substituted heteroarylamino wherein substituted heteroaryl is R¹¹⁰;(94) mono- and di-heterocyclic amino wherein heterocyclic is R¹⁰⁵; and(95) mono- and di-substituted heterocyclic amino wherein substitutedheterocyclic is R¹⁰⁶; R²⁰¹ is a member selected from (1) hydroxyl; (2)acyl; (3) acylamino; (4) thiocarbonylamino; (5) acyloxy; (6) R¹⁰¹; (7)R¹⁰²; (8) alkoxy; (9) substituted alkoxy; (10) R¹¹¹; (11) R¹¹²; (12)R¹¹³; (13) R¹¹⁴; (14) amidino; (15) alkylamidino, wherein alkyl is R¹⁰¹;(16) thioamidino; (17) amino; (18) aminoacyl; (19) aminocarbonyloxy;(20) aminocarbonylamino; (21) aminothiocarbonylamino; (22) R¹⁰⁷; (23)R¹⁰⁸; (24) aryloxy; (25) substituted aryloxy; (26) cycloalkoxy; (27)substituted cycloalkoxy; (28) heteroaryloxy; (29) substitutedheteroaryloxy; (30) heterocyclyloxy; (31) substituted heterocyclyloxy;(32) carboxyl; (33) carboxylalkyl wherein alkyl is R¹⁰¹; (34)carboxyl-substituted alkyl wherein substituted alkyl is R¹⁰²; (35)carboxyl-cycloalkyl wherein cycloalkyl is R¹⁰³; (36)carboxyl-substituted cycloalkyl wherein substituted cycloalkyl is R¹⁰⁴;(37) carboxylaryl wherein aryl is R¹⁰⁷; (38) carboxyl-substituted arylwherein substituted aryl is R¹⁰⁸; (39) carboxylheteroaryl whereinheteroaryl is R¹⁰⁹; (40) carboxyl-substituted heteroaryl whereinsubstituted heteroaryl is R¹¹⁰; (41) carboxylheterocyclic whereinheterocyclic is R¹⁰⁵; (42) carboxyl-substituted heterocyclic whereinsubstituted heterocyclic is R¹⁰⁶; (43) carboxylamido; (44) cyano; (45)thiol having the formula —SH; (46) thioalkyl; (47) substitutedthioalkyl; (48) thioaryl; (49) substituted thioaryl (50) thioheteroaryl;(51) substituted thioheteroaryl; (52) thiocycloalkyl; (53) substitutedthiocycloalkyl; (54) thioheterocyclic; (55) substitutedthioheterocyclic; (56) R¹⁰³; (57) R¹⁰⁴; (58) guanidino; (59)guanidinosulfone; (60) halogen; (61) nitro; (62) R¹⁰⁹; (63) R¹¹⁰; (64)R¹⁰⁵; (65) R¹⁰⁶; (66) cycloalkoxy; (67) substituted cycloalkoxy; (68)heteroaryloxy; (69) substituted heteroaryloxy; (70) heterocyclyloxy;(71) substituted heterocyclyloxy; (72) oxycarbonylamino; (73)oxythiocarbonylamino; (74) —S(O)₂-alkyl wherein alkyl is R¹⁰¹; (75)—S(O)₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (76)—S(O)₂-cycloalkyl wherein cycloalkyl is R¹⁰³; (77) —S(O)₂-substitutedcycloalkyl wherein substituted cycloalkyl is R¹⁰⁴; (78) —S(O)₂-alkenylwherein alkenyl is R¹¹¹; (79) —S(O)₂-substituted alkenyl whereinsubstituted alkenyl is R¹¹²; (80) —S(O)₂-aryl wherein aryl is R¹⁰⁷; (81)—S(O)₂-substituted aryl wherein substituted aryl is R¹⁰⁸; (82)—S(O)₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (83) —S(O)₂-substitutedheteroaryl wherein substituted heteroaryl is R¹¹⁰; (84)—S(O)₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (85)—S(O)₂-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶; (86) —OS(O)₂-alkyl wherein alkyl is R¹⁰¹; (87) —OS(O)₂-substitutedalkyl wherein substituted alkyl is R¹⁰²; (88) —OS(O)₂-aryl wherein arylis R¹⁰⁷; (89) —OS(O)₂-substituted aryl wherein substituted aryl is R¹⁰⁸;(90) —OS(O)₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (91)—OS(O)₂-substituted heteroaryl wherein substituted heteroaryl is R¹¹⁰;(92) —OS(O)₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (93)—OS(O)₂-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶; (94) —OSO₂—NRR where R is hydrogen or R¹⁰¹; (95) —NRS(O)₂-alkylwherein alkyl is R¹⁰¹; (96) —NRS(O)₂-substituted alkyl whereinsubstituted alkyl is R¹⁰²; (97) —NRS(O)₂-aryl wherein aryl is R¹⁰⁷; (98)—NRS(O)₂-substituted aryl wherein substituted aryl is R¹⁰⁸; (99)—NRS(O)₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (100)—NRS(O)₂-substituted heteroaryl wherein substituted heteroaryl is R¹¹⁰;(101) —NRS(O)₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (102)—NRS(O)₂-substituted heterocyclic wherein substituted heterocyclic isR¹⁰⁶; (103) —NRS(O)₂—NR-alkyl wherein alkyl is R¹⁰¹; (104)—NRS(O)₂—NR-substituted alkyl wherein substituted alkyl is R¹⁰²; (105)—NRS(O)₂—NR-aryl wherein aryl is R¹⁰⁷; (106) —NRS(O)₂—NR-substitutedaryl wherein substituted aryl is R¹⁰⁸; (107) —NRS(O)₂—NR-heteroarylwherein heteroaryl is R¹⁰⁹; (108) —NRS(O)₂—NR-substituted heteroarylwherein substituted heteroaryl is R¹¹⁰; (109) —NRS(O)₂—NR-heterocyclicwherein heterocyclic is R¹⁰⁵; (110) —NRS(O)₂—NR-substituted heterocyclicwherein substituted heterocyclic is R¹⁰⁶, (111) mono- and di-alkylamino,wherein alkyl is R¹⁰¹; (112) mono- and di-(substituted alkyl)amino,wherein substituted alkyl is R¹⁰²; (113) mono- and di-arylamino whereinaryl is R¹⁰⁷; (114) mono- and di-substituted arylamino whereinsubstituted aryl is R¹⁰⁸; (115) mono- and di-heteroarylamino whereinheteroaryl is R¹⁰⁹; (116) mono- and di-substituted heteroarylaminowherein substituted heteroaryl is R¹¹⁰; (117) mono- and di-heterocyclicamino wherein heterocyclic is R¹⁰⁵; (118) mono- and di-substitutedheterocyclic amino wherein substituted heterocyclic is R¹⁰⁶; R³⁰⁰ is amember selected from (i) —SO₂-alkyl wherein alkyl is R¹⁰¹; (ii)—SO₂-substituted alkyl wherein substituted alkyl is R¹⁰²; (iii)—SO₂-alkenyl wherein alkenyl is R¹¹¹; (iv) —SO₂-substituted alkenylwherein substituted alkenyl is R¹¹²; (v) —SO₂-cycloalkyl whereincycloalkyl is R¹⁰³; (vi) —SO₂-substituted cycloalkyl wherein substitutedcycloalkyl is R¹⁰⁴. (vii) —SO₂-aryl wherein aryl is R¹⁰⁷; (viii)—SO₂-substituted aryl wherein substituted aryl is R¹⁰⁸;(ix)-SO₂-heteroaryl wherein heteroaryl is R¹⁰⁹; (x) —SO₂-substitutedheteroaryl wherein substituted heteroaryl is R¹¹⁰; (xi)—SO₂-heterocyclic wherein heterocyclic is R¹⁰⁵; (xii) —SO₂-substitutedheterocyclic wherein substituted heterocyclic is R¹⁰⁶; and (xiii)—SO₂NRR; alkoxy has the formula “alkyl-O—”, wherein alkyl is R¹⁰¹;substituted alkoxy has the formula “substituted alkyl-O—”, whereinsubstituted alkyl is R¹⁰²; cycloalkoxy has the formula “—O-cycloalkyl”,wherein cycloalkyl is R¹⁰³; substituted cycloalkoxy has the formula“—O-substituted cycloalkyl”, wherein substituted cycloalkyl is R¹⁰⁴;alkenoxy has the formula “alkenyl-O—”, wherein alkenyl is R¹¹¹;substituted alkenoxy has the formula “substituted alkenyl-O—”, whereinsubstituted alkenyl is R¹¹²; cycloalkenoxy has the formula“cycloalkenyl-O—”, wherein cycloalkenyl is R¹¹⁵; substitutedcycloalkenoxy has the formula “substituted cycloalkenyl-O—”, whereinsubstituted cycloalkenyl is R¹¹⁶; aryloxy has the formula “aryl-O—”,wherein aryl is R¹⁰⁷; substituted aryloxy has the formula “substitutedaryl-O—”, wherein substituted aryl is R¹⁰⁸; heteroaryloxy has theformula “—O-heteroaryl”, wherein heteroaryl is R¹⁰⁹; substitutedheteroaryloxy has the formula “—O-substituted heteroaryl”, whereinsubstituted heteroaryl is R¹¹⁰; heterocyclyloxy has the formula“—O-heterocyclic”, wherein heterocyclic is R¹⁰⁵; substitutedheterocyclyloxy has the formula “—O-substituted heterocyclic”, whereinsubstituted heterocyclic is R¹⁰⁶; aryloxyaryl has the formula“aryl-O-aryl”, wherein each aryl is R¹⁰⁷; substituted aryloxyaryl hasthe formula “aryl-O-aryl”, wherein each aryl is R¹⁰⁷, substituted on oneor both aryl rings with from 1 to 3 substituents selected from the groupconsisting of (1) R²⁰¹; (2) unsymmetric di-substituted amines havingdifferent substituents selected from the group consisting of R¹⁰¹, R¹⁰²,R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹⁰⁵ and R¹⁰⁶; (3) amino groups blocked byblocking groups selected from tert-butyloxycarbonyl (Boc),carbobenzyloxy (Cbz) and formyl; and (4) —SO₂NRR; acyl is R^(c)—C(O)—;acylamino is selected from the group —C(O)NR^(c)R^(c), wherein eachR^(c) is optionally joined to form together with the nitrogen atom aheterocyclic or substituted heterocyclic ring, wherein heterocyclic isR¹⁰⁵ and substituted heterocyclic is R¹⁰⁶; thiocarbonylamino is selectedfrom the group —C(S)NR^(c)R^(c), wherein each R^(c) is optionally joinedto form together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring, wherein heterocyclic is R¹⁰⁵ and substitutedheterocyclic R¹⁰⁶; acyloxy is selected from R^(b)—C(O)O—; oxysulfonylhas the formula R^(b)—SO₂O—; amino has the formula —NH₂; substitutedamino has the formula —NR^(d)R^(d), where each R^(d) is independentlyselected from the group consisting of hydrogen, R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴,R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, D¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹², R¹¹³, R¹¹⁴ and—SO₂—R^(e), wherein R^(e) is a member selected from R¹⁰¹, R¹⁰², R¹⁰³,R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹ and R¹¹²; or the R^(d)groups can be joined together with the nitrogen atom to form aheterocyclic or a substituted heterocyclic ring, wherein heterocyclic isR¹⁰⁵ and substituted heterocyclic is R¹⁰⁶, provided that both R^(d)groups are not hydrogen; amidino has the formula H₂NC(═NH)—; alkylamidino is “alkylHNC(═NH)—”, wherein alkyl is R¹⁰¹; thioamidino has theformula RSC(═NH)—; aminoacyl has the formula —NRC(O)R^(b); aminosulfonylhaving the formula —NRSO₂R^(b); aminocarbonyloxy having the formula—NRC(O)O—R^(b); aminosulfonyloxy has the formula —NRSO₂O—R^(b);oxycarbonylamino has the formula —OC(O)NH₂, —OC(O)NRR or —OC(O)NRR^(b),wherein each R is optionally joined to form together with the nitrogenatom a heterocyclic or substituted heterocyclic ring, whereinheterocyclic is R¹⁰⁵ and substituted heterocyclic is R¹⁰⁶;oxythiocarbonylamino has the formula —OC(S)NH₂, —OC(S)NRR or—OC(S)NRR^(b), wherein each R is optionally joined to form together withthe nitrogen atom a heterocyclic or substituted heterocyclic ring,wherein heterocyclic is R¹⁰⁵ and substituted heterocyclic is R¹⁰⁶;aminocarbonylamino has the formula —NR^(f)C(O)NR^(f)R^(f) or—NR^(f)C(O)NR^(f)R^(b), wherein each R^(f) is optionally joined to formtogether with the nitrogen atom a heterocyclic or substitutedheterocyclic ring, wherein heterocyclic is R¹⁰⁵ and substitutedheterocyclic is R¹⁰⁶; aminothiocarbonylamino has the formula—NR^(f)C(S)NR^(f)R^(f) or —NR^(f)C(S)NR^(f)R^(b), wherein each R^(f) isoptionally joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring, wherein heterocyclic is R¹⁰⁵ andsubstituted heterocyclic is R¹⁰⁶; aminosulfonylamino has the formula—NR^(f)SO₂NR^(f)R^(f) or —NR^(f)SO₂NR^(f)R^(b), wherein each R^(f) isoptionally joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring, wherein heterocyclic is R¹⁰⁵ andsubstituted heterocyclic is R¹⁰⁶; oxysulfonylamino has the formula—OSO₂NH₂, —OSO₂NRR or —OSO₇NRR^(b), wherein each R is optionally joinedto form together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring, wherein heterocyclic is R¹⁰⁵ and substitutedheterocyclic is R¹⁰⁶; halogen is fluoro, chloro, bromo or iodo;guanidino has the formula —NR^(f)C(═NR)NR^(f)R^(f) or—NR^(f)C(═NR^(f)NR^(f)R^(b); guanidinosulfone has the formula—NRC(═NR)NRSO₂—R^(b); thioalkyl having the formula “—S-alkyl”, whereinalkyl is R¹⁰¹; substituted thioalkyl has the formula “—S-substitutedalkyl”, wherein substituted alkyl is R¹⁰²; thiocycloalkyl has theformula “—S-cycloalkyl”, wherein cycloalkyl is R¹⁰³; substitutedthiocycloalkyl has the formula “—S-substituted cycloalkyl”, whereinsubstituted cycloalkyl is R¹⁰⁴; thioaryl has the formula “—S-aryl”,wherein aryl is R¹⁰⁷; substituted thioaryl has the formula“—S-substituted aryl”, wherein substituted aryl is R¹⁰⁸; thioheteroarylhas the formula “—S-heteroaryl”, wherein heteroaryl is R¹⁰⁹; substitutedthioheteroaryl has the formula “—S-substituted heteroaryl”, whereinsubstituted heteroaryl is 8110; thioheterocyclic has the formula“—S-heterocyclic”, wherein heterocyclic is R^(10D); and substitutedthioheterocyclic has the formula “—S-substituted heterocyclic”, whereinsubstituted heterocyclic is R¹⁰⁶; wherein each R is independentlyhydrogen or R¹⁰¹; each R^(b) is a member independently selected fromR¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹²,R¹¹³ and R¹¹⁴; each R^(c) is a member independently selected from H,R¹⁰¹, R¹⁰², R¹⁰³, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, R¹¹¹, R¹¹²,R¹¹³ and R¹¹⁴; and each R^(f) is independently hydrogen, R¹⁰¹ or ablocking group selected from tert-butyloxycarbonyl (Boc), carbobenzyloxy(Cbz) and formyl.